This meta-analysis of studies using 5D‑ASC, 11‑ASC and MEQ30 establishes dose–response curves for LSD up to 200 μg, finding sigmoid‑like increases in subjective effects that plateau at around 100 μg. The strongest dose‑dependent effects were perceptual changes and illusory imagination, followed by positive ego‑dissolution, while anxiety and dread remained minimal, and substantial variability points to important non‑pharmacological influences.
Lysergic acid diethylamide (LSD) is a potent classic serotonergic psychedelic, which facilitates a variety of altered states of consciousness. Here we present the first meta-analysis establishing dose-response relationship estimates of the altered states of consciousness induced by LSD. Data extracted from articles identified by a systematic literature review following PRISMA guidelines were obtained from the Altered States Database. The psychometric data comprised ratings of subjective effects from standardized and validated questionnaires: the Altered States of Consciousness Rating Scale (5D-ASC, 11-ASC) and the Mystical Experience Questionnaire (MEQ30). We performed meta-regression analyses using restricted cubic splines for data from studies with LSD doses of up to 200 μg base. Most scales revealed a sigmoid-like increase of effects, with a plateauing at around 100 μg. The most strongly modulated factors referred to changes in perception and illusory imagination, followed by positively experienced ego-dissolution, while only small effects were found for Anxiety and Dread of Ego Dissolution. The considerable variability observed in most factors and scales points to the role of non-pharmacological factors in shaping subjective experiences. The established dose-response relationships may be used as general references for future experimental and clinical research on LSD to compare observed with expected subjective effects and to elucidate phenomenological differences between psychedelics.
Prugger and colleagues situate LSD within the class of classic serotonergic psychedelics, noting that these substances principally act at the 5-HT2A receptor but differ in molecular structure and broader pharmacology. Earlier research has produced extensive descriptive and clinical literature on LSD from the 1950s–1970s, followed by a research hiatus and a more recent focus on other psychedelics such as psilocybin and N,N-DMT. The authors highlight that acute psychedelic effects are temporally dynamic and that the intensity and quality of the acute experience may predict therapeutic outcomes, so characterising dose-dependent subjective effects is clinically and experimentally important. They also note that contemporary experimental doses are generally lower than many historical studies and that no prior meta-analysis has quantified dose-response relationships for LSD-induced subjective experiences using modern psychometric instruments. The present study therefore aims to estimate dose-response relationships between LSD dose (within a range of 25 µg to 200 µg) and the intensity and quality of acute subjective experiences in healthy, highly selected participants. Using psychometric data from validated questionnaires aggregated in the Altered States Database (ASDB), the investigators seek to provide reference dose-response estimates for commonly used scales measuring altered states of consciousness, to support future experimental and clinical research on low to moderate LSD dosages.
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Majic, T., Schmidt, T. T., Gallinat, J. · Journal of Clinical Psychopharmacology (2015)
This work is a meta-analysis drawing on psychometric questionnaire data stored in the ASDB (version ASDB-v2.0_12-2021) and updated literature through June 2022. Included sources were MEDLINE-listed studies published between 1975 and 2022 that reported standardized retrospective ratings of LSD-induced subjective effects. Data were excluded if the experimental conditions involved co-administration of other substances (for example ketanserin pre-treatment), if LSD was administered as microdoses (< 25 µg), if dosage was unclear, or if data reflected recreational use. Two reports were excluded as duplicates of previously published data, and one patient dataset (N = 11) was identified but not analysed. Where necessary, the study team obtained unpublished questionnaire ratings from authors and adjusted dose values in some reports following consultation, reflecting issues with unstable capsule formulations. The meta-analysis used ratings from three questionnaires: the Altered States of Consciousness Rating Scale in its 5D-ASC and 11-ASC formats, and the MEQ30 (Mystical Experience Questionnaire). The 5D-ASC organises items into five primary dimensions, while the 11-ASC and MEQ30 provide more granular scales; the MEQ30 comprises four subscales (Mystical, Positive Mood, Transcendence of time and space, Ineffability). Reliability estimates for these instruments are reported as acceptable to very good in the source text. For statistical analysis the investigators applied linear meta-regression models with random effects to approximate dose-response relationships across the available dose range. Because the full sigmoid functional form could not be estimated given limited dose extremes, linear models were used as approximations. To accommodate multiple effect sizes from within-subject designs and repeated measures, the robust variance estimation (RVE) framework with small-sample adjustment was employed, assuming a common within-study correlation p (default p = 0.8) and conducting sensitivity analyses to assess dependence of estimates on p. Weights were computed using a correlated effects model with inverse-variance weighting and a method-of-moments estimator. Heterogeneity was assessed with I2 and Tau2. Analyses were performed in R (version 4.2.1) using the robumeta package; visualization included radar charts and dose-response plots, and the analysis syntax was made available on Github.
Fourteen studies in healthy participants were included in the analysis, yielding an overall sample of N = 322. Available psychometric data covered LSD doses between 25 µg and 200 µg and contained questionnaire ratings from the 5D-ASC, 11-ASC and MEQ30, with some datasets providing multiple questionnaire applications and a few unpublished scale scores added after author correspondence. Across most questionnaire factors and scales, higher LSD doses were associated with increased ratings of subjective effects. The strongest dose-related increases were observed for visionary phenomena, notably audiovisual synesthesia and altered imagery. Measures reflecting positively experienced ego-dissolution phenomena (depersonalisation and derealisation components) also showed dose-related increases, albeit less pronounced than the visual phenomena. In contrast, scales indexing mystical or spiritual-type experiences (MEQ30 Mystical subscale and related measures) exhibited only weak modulation by dose within the examined range. Heterogeneity metrics varied by scale. Tau2, the between-study variance, was reported as rather small for most factors and scales, but I2 indicated considerable inconsistency (60%–91%) for many scales; only Anxiety on the 11-ASC and Mystical on the MEQ30 showed small-to-moderate inconsistency (< 60%). The investigators performed sensitivity analyses regarding the assumed within-study correlation parameter p, though the extracted text does not report the detailed outcome of those tests. Administration route varied across studies (mostly oral, with one intravenous and one sublingual study), but analyses did not stratify by route or formulation.
Prugger and colleagues interpret their findings as evidence that, in controlled laboratory settings with healthy, highly selected participants, small to moderate doses of LSD (25–200 µg) reliably increase most characteristics of altered states of consciousness measured by standard questionnaires. They emphasise that within this dose range LSD most potently modulated visual-perceptual phenomena and aspects of positively experienced ego-dissolution, while mystical-type experiences were less dose-sensitive and therefore may depend more on extra-pharmacological factors such as set and setting, personality, preparation and intentions. The authors compare their dose-response pattern to a previously published psilocybin meta-analysis and report broadly similar profiles, but note two notable differences: LSD produced stronger, more dose-sensitive effects for audio-visual synesthesia, and relatively weaker, less dose-dependent effects on mystical-type scales compared with psilocybin. They discuss the possibility that LSD's broader receptor interaction profile, beyond 5-HT2A, might contribute to its distinctive propensity to induce synesthesia, while acknowledging that extra-pharmacological factors could also explain differences between substances. The manuscript further raises the point that pronounced synesthesia with LSD has been discussed in relation to rare long-term perceptual disorders such as hallucinogen-persistent perception disorder, but the authors caution that prevalence data are confounded by LSD's widespread recreational use. Key limitations acknowledged by the investigators include reliance on self-report measures to quantify private subjective states, considerable unexplained variance likely driven by heterogeneous set and setting across studies, a relatively small number of studies and datasets limiting generalisability, and incomplete coverage of very low and very high doses that prevents fitting a full sigmoid dose-response curve. They additionally note that RVE allows inclusion of dependent effect sizes but is not optimised for precise estimation of heterogeneity parameters, and that varying administration routes and formulations were not modelled separately. Given these constraints and observed heterogeneity, the authors advise treating dose-response estimates cautiously and highlight the need for more standardised reporting of extra-pharmacological variables in future research.
LSD administration in healthy, carefully screened participants in controlled settings increased most measured dimensions of altered states of consciousness within the examined 25–200 µg range. The subjective profile of small to moderate LSD doses was dominated by visual alterations and positively experienced ego-dissolution, while mystical-type experiences showed weaker dose-dependence. Despite variability across studies, the authors present these dose-response estimates as a general reference for relating observed subjective effects to expected dose-specific effects in future experimental and clinical work.
D-lysergic acid diethylamide (LSD) is the prototype of classic serotonergic psychedelics, a group of substances which unfold their psychoactive properties predominantly via the serotonin 2A (5-HT2A) receptor. Psychedelics embrace structurally heterogenous subgroups like phenethylamines (e.g., mescaline) and tryptamines (e.g., psilocybin, N,N-dimethyltryptamine (N,N-DMT)), as well as substances from the ergoline subgroup (e.g., LSD and lysergic amide (LSA)) which have been characterized as "rigidified tryptamines". The term 'psychedelics' is also used in a broader sense, including non-serotonergic drugs like Ketamine, PCP or MDMA. The term 'psychedelic experience' is used in an even broader sense, not limited to the effects induced by specific substances, instead referring to a group of psychological effects. However, there is no clear definition on the exact set of consciousness alterations that define a psychedelic experience. Here, we will refer to classic serotonergic psychedelics and the effects they induce when using the term 'psychedelics' or 'psychedelic experience'. Several studies suggest that qualitatively, LSD might not be differentiated from other psychedelics with regard to the induced psychologic effects. On the other hand, anecdotal reports mention differences in subjective experiences regarding different substances, and LSD somewhat differs from pharmacodynamical profiles of other 5-HT2A agonists, including a broader variety of receptor targets. After its initial synthesis in 1938, LSD's psychedelic properties have accidentally been discovered in 1943 by the Swiss pharmacologist Albert Hofmann. Ever since, LSD has been the most extensively investigated psychedelic from the 1950s to the 1970s, with more than 1,000 scientific papers published in the context of basic science, as well as in clinical research as a therapeutic tool. Most intensively studied indications included, among others, alcoholismand existential distress in lifethreatening physical illness. After a hiatus of more than 20 years, during which regulatory hurdles prevented research on psychedelics, research eventually resumed in the 1990s, with a focus shifting from LSD to other substances like psilocybinand N,N-dimethyltryptamine (N,N-DMT). This shift might have taken place due to political aspects given a somewhat notorious image of LSD, as well as pragmatic considerations, as psychoactive effects of LSD display longer duration than the latter substances. In recreational underground use, however, LSD is still by far the most frequently used psychedelic worldwide, and dosages of psychedelics are often compared to LSD equivalents by users. LSD has recently been re-evaluated for the treatment of different mental health conditions, like anxiety and depression in patients withand without lifethreatening illness. Psychological effects of psychedelics underlie specific temporal dynamics, including (acute) psychedelic experiences, subacute effects ("afterglow phenomena" or "carry-over effects") and long-term (enduring) effects. There is some evidence that the quality and intensity of acute psychedelic effects might predict therapeutic outcome. Thus, the classification and description of acute psychedelic experiences appear to be of high importance when it comes to optimizing treatment interventions regarding efficacy and safety. In order to determine the optimal dosing ranges of LSD for future clinical studies, first and most importantly the influence of the LSD dosage on the nature and intensity of acute subjective effects needs characterization. Of note, the range of LSD dosages employed in current research is on average markedly below the dosages administered in studies from the 1950-1970s, where sometimes dosages of 1,000 ug and more have been administered. Only few studies to date have investigated the dose dependency of altered states induced by LSDor have compared therapeutic effects in different dosages of psychedelics (e.g.). As LSD has only recently returned to basic and clinical research, only few studies have been carried out according to modern research standards, while the studies from the 1950s to the 1970s exhibit strong methodological limitations and do not appear suited for study overarching comparisons. Over the last decades some gold standards for the assessment of altered states phenomena have been established in terms of several well-validated questionnaires for an retrospective assessment of altered experiences. Such standardized assessment allows meta-analytic comparisons, as recently presented to establish dose-response relationships for altered experiences induced by psilocybin. To date there is no meta-analysis available investigating dose-response relationships for the subjective experiences of LSD. With the present meta-analysis, we aim to obtain estimates of the relationship between LSD dosages and the intensity and quality of psychedelic experiences in healthy subjects. The data stem from the Altered States Database (ASDB,,), which is a regularly updated database with questionnaire data extracted from articles identified by systematic literature research, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Statement Guidelines. Available data was found for the Altered States of Consciousness Rating Scale (5D-ASC, 11-ASC) and the Mystical Experience Questionnaire (MEQ30), as well as for a dosage range of 25 ug to 200 ug.
Psychometric questionnaire data on the subjective experience of LSD were included in this meta-analysis. The data has been retrieved from the ASDB repository on Open Science Framework (OSF;, version: "ASDB-v2.0_12-2021"), which contains data from MEDLINE-listed studies published from 1975 until 2021-12-31. The ASDB data is based on a systematic literature review following PRISMA standardsas described in Prugger et al.. Here, only datasets investigating the subjective effects of LSD were retrieved. To include most recent data, the described literature review was extended to contain data published until 2022-06-31. Further information on the search strategy and the PRISMA flowchart showing the process of item identification and screening can be found in Supplementary Material. Data were excluded if experimental conditions comprised applications of combinations of substancessuch as pre-treatments with ketanserin; if the application of LSD was reported as microdosing (< 25 μg), if the LSD dosage was unclear, and if data were about recreational LSD usage. Two studieshave been excluded as they reported on previously published data. From studies reporting multiple questionnaire applications at different time points during the same day of the experimental session, only the final and complete questionnaire application was included describing the overall experience. In addition, unpublished original data were obtained from the authorsof ratings on the 11-ASC dimensions Changed Meaning of Percepts and Elementary Imagery which were not reported in the original publication. Also, after consultation with the authors, the LSD dose in a series of reportswere adjusted as suggested in, due to administration of capsules containing an unstable LSD formulation leading to dispersion of lower than presumed LSD doses. Additionally, one dataset reporting on LSD application in a population of patients with anxiety associated with life-threatening diseases (N = 11, MEQ30, 140 µg)was found, however not included in the analysis.
This meta-analysis included psychometric data from commonly applied questionnaires to assess the phenomenology of altered states of consciousness, namely from two versions of the Altered States of Consciousness Rating Scale (the 5D-ASC and the 11-ASC), and from the Mystical Experience Questionnaire (MEQ30). The Altered States of Consciousness Rating Scaleis a self-report questionnaire with 94 items rated on a visual analog scale. Two different analysis schemata are in use: In the 5D-ASC version ("5-Dimensional Altered States of Consciousness Rating Scale"), items are assigned to five core dimensions:); 11-ASC: mean Cronbach's alpha of 0.83). The Mystical Experience Questionnaire, in its latest version the MEQ30, consists of 30 items assigned to four scales: (1) Mystical, (2) Positive Mood, (3) Transcendence of time and space, and (4) Ineffability. This factor structure is currently recommended for analyses and has been assessed for reliability, yielding very good scores for all four subscales (Cronbach's alpha: 0.80 to 0.95). A more detailed description of the questionnaires can be found in Schmidt and Majić,and in a recent review by de Deus Pontual et al. (2022).
The statistical analyses were conducted as previously applied in Hirschfeld and Schmidt (2021): Due to a lack of data for minimum and maximum doses, a linear meta-regression for each factor and scale of the respective questionnaires was performed to approximate the dynamic range of a dose-response relationship, which is usually best described by a sigmoid function. Intercept and slope parameters were obtained with a random effects model to address between-study variance. To account for statistical dependencies resulting from within-subject designs with repeated measures, the robust variance estimation (RVE) frameworkwith small sample adjustmentwas used. The RVE framework permits the inclusion of multiple effect size estimates from a study without the knowledge of the underlying covariance structure by assuming a common correlation p (0-1) between within-study effect sizes (p= .8 was used as the recommended default value). To test whether the choice of p affected the obtained parameter estimates, a sensitivity analysis was performed. The weights were calculated using the correlated effects model with the inverse of the sampling variance in combination with a method of moments estimator. Heterogeneity was assessed by estimating the degree of inconsistency across studies using I 2and the between-study variance with Tau 2. Analyses were performed using the robumeta packagein R version 4.2.1. To provide an overview of results, radar charts for each questionnaire were computed using the fmsb package. Additionally, for each scale dose-response relationships were computed using the plot function in R version 4.2.1.The individual effect sizes are shown as circles corresponding to the magnitude of the calculated weight of a study sample. All syntax is provided on Github ().
Eleven studies from the ASDB were included in the analysis. The additional literature search identified three studies. Thus, a total of 14 studies in healthy participants (overall N = 322) were included (See Table) comprising 13 datasets, or questionnaire applications, from seven samples of participants for the 5D-ASC;) -placebo-controlled, cross-over, within-subject, balanced-order, double-dummy -fMRI and MEG (data published in other study), further questionnaire assessment), who noted that the subjective effects of LSD may not be primarily characterized by mystical and spiritual experiences, with the possible explanation that these findings are highly depend on the set and setting used in the study. In contrast, the study bysuggests that doses as low as 50 µg may already evoke full mystical-type experiences in certain individuals, depending on the set and setting. Taken together, mystical-type experiences may be less predicted by LSD dose than by extra-pharmacological factors.
Not only the LSD dose (substance), but also the environment of substance administration (setting) as well as each substance user's personality and the preparation, expectation and intention of substance use (set) are essential factors in shaping the subjective experience induced by psychedelicsand can lead to considerable inter-and intra-individual variability. The experimental settings of the included studies are highly different.reports of "living-room style" environments with possibilities to relax, read or watch movies between measurements, similar to Kraehenmann et al. (2017) ("in an esthetic living-roomlike room")and de Wit et al. (). In other studies, however, participants were also given tasks during LSD applications that involved greater effort, potentially inhibiting the manifestation of effects. Previous work indicated that spatially constrained neuroimaging procedures may be demanding for some individuals and could increase the likelihood of challenging experiences. Carhart-Harris et al. (2016) reported on fMRI and MEG measurements of over 60 min each, as well as previous MRI environment habituation and a subsequent battery of cognitive and behavioral tests. From the studies included, also2022) reported on "quiet standard hospital patient room" environments, and the study procedure by Family et al. (2022)included a 60-minutes breathing exercise. Additional factors influencing the psychedelic experience and thereby increasing the variability within and between the given datasets may involve subject's age, previous experience with psychedelics or other mind-altering substances, as well as differences in individual pharmacokinetics. The study by, in contrast to the results of this meta-analysis. In summary, the results of the few dose-response reports available to date are largely consistent with those presented here. Comparison to dose-response relationships of psilocybin-induced subjective experiences Psilocybin and LSD are both classic psychedelics primarily targeting the 5-HT2A receptor neurotransmission, so it is thought that they share typical psychedelic effects. The meta-analysis presented here yielded an overall relatively similar pattern of response to those of the psilocybin meta-analysis. Audio-Visual Synesthesia compared to psilocybin, supporting previous reports that LSD is highly effective in inducing synesthesia. In a survey among recreational psychedelic users, the highest incidence rate of drug-induced synesthesia was reported for LSDand a study comparing the effects of LSD (1 μg/kg) and psilocybin (150 μg/kg) also found significantly more synesthesia in the LSD group. Considering that LSD not only interacts with serotonin receptors, but with dopaminergic and adrenergic receptors, our results could be interpreted in line with evidence that drug-induced synesthesia is not exclusively a result of serotonergic activation. LSD's pronounced modulation of Audio-Visual Synesthesia via non-5-HT2A mechanism of action may be associated with the etiology of the rarely occurring hallucinogen-persistent perception disorder (HPPD). The vast majority of case reports on HPPD have been associated with LSD, even if it has to be taken into account that LSD is also the most frequently used psychedelic worldwide. Generally, observed differences between LSD and psilocybin could either be attributed to extra-pharmacological factors such as set and setting or pharmacological differences resulting from molecular structures with different profiles of receptor activity, durations of action, and potentially different functional selectivity and potency.
The estimation of dose-response relationships of subjective LSD experiences is associated with different challenges. First, the assessment of subjective experiences always faces problems associated with the quantification of personal and private inner states, relying on self-reporting. This makes its assessment more difficult than that of other physiological parameters. The unexplained variance in subjective responses was relatively large, so that the influences of set and setting should be considered when interpreting or applying the results of this analysis. A more standardized assessment of factors other than substance dose could improve comparability of future studies. Also, the generalizability of the results presented here is limited due to the small number of studies available and the results obtained do not necessarily apply to the general population or to recreational use outside controlled laboratory experiments. Moreover, although RVE allows the inclusion of statistically dependent effect sizes (due to repeated measures) to obtain reliable meta-regression estimates, it is not designed to provide precise variance parameter estimates or to test null-hypotheses related to heterogeneity parameters. Another limitation of this meta-analysis is that, while LSD was administered orally in most studies, it was administered intravenously in one studyand sublingually in another study. There were no different treatments in the analysis depending on substance administration method or substance formulation, although it has been indicated that different administration methods and substance formulations can have different physiological and subjective effects. Also, the included LSD doses did not sufficiently cover the upper and lower bounds to estimate a sigmoid curve, so responses at very high and very low doses cannot be predicted by applying the models identified in this analysis. The robustness of the obtained estimates, have been discussed in the previous meta-analysis on the effects of psilocybin by Hirschfeld and Schmidt (2021). With 12 to 19 datasets, the amount of available data in the present analysis was in the recommended range. The between-study variance, Tau 2 , was rather small for most factors and scales (see Table). The degree of inconsistency across studies, I 2 , is considered small to moderate if < 60%, which was the case only for Anxiety on the 11-ASC and Mystical on the MEQ30. For the other factors and scales considerable inconsistencies were found (60 -91%). Until more data are available for these scales, the corresponding dose-response estimates need to be treated with caution, and confidence intervals should be considered.
LSD administration in healthy, highly selected study participants in a controlled setting intensified almost all characteristics of ASC assessed with the two given questionnaires. The subjective experience of small to moderate dosages of LSD was mainly characterized by alterations in visual perception and positively experienced ego dissolution. Compared to psilocybin, LSD elicits very similar effects, however it seems to evoke larger effects with stronger dose-modulation for audio-visual synesthesia and smaller effects with weaker dose-modulation for spiritual or mystical-type experiences. Despite extra-pharmacological differences between included studies, we established relative robust dose-response relationships for most factors and scales. Results may be used as a general reference to relate observed with expected dose-specific effects.
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