Study Design

We pooled data from two similar studies using double-blind, placebo-controlled, crossover designs with two experimental test sessions (LSD and placebo) in a balanced order. Study 1 used a dose of 100 μg LSD and placebo in 24 subjects. Study 2 used 200 μg LSD or placebo in 16 subjects. The washout periods between sessions were at least 7 days. The studies were conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee. The administration of LSD to healthy subjects was authorized by the Swiss Federal Office for Public Health, Bern, Switzerland. All of the subjects provided written consent before participating in either of the studies, and they were paid for their participation. The studies were registered at ClinicalTrials.gov (NCT02308969, NCT01878942). The subjective, endocrine, and pharmacokinetic effects of LSD in Study 2 were previously reported (Dolder et al, 2015b; Schmid et al, 2015; Strajhar et al, 2016).

Participants

Forty healthy participants were recruited from the University of Basel campus via online advertisement. Twenty-four subjects (12 men, 12 women; 33±11 years old (mean±SD); range, 25–60 years) participated in Study 1, and 16 subjects (8 men, 8 women; 29±6 years old; range, 25–51 years) participated in Study 2. The inclusion and exclusion criteria were identical for both studies. Subjects younger than 25 years of age were excluded from participating in the study. Additional exclusion criteria were age >65 years, pregnancy (urine pregnancy test at screening and before each test session), personal or family (first-degree relative) history of major psychiatric disorders (assessed by the semistructured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Axis I disorders by the study physician and an additional interview by a trained psychiatrist), use of medications that may interfere with the study medication, chronic or acute physical illness (abnormal physical exam, electrocardiogram, or hematological and chemical blood analyses), tobacco smoking (>10 cigarettes/day), lifetime prevalence of illicit drug use >10 times (except for tetrahydrocannabinol), illicit drug use within the last 2 months, and illicit drug use during the study (determined by urine drug tests). The subjects were asked to abstain from excessive alcohol consumption between test sessions and particularly limit their use to one standard drink on the day before the test sessions. Additionally, the participants were not allowed to drink xanthine-containing liquids after midnight before the study day. Eleven subjects had used a hallucinogen including LSD (6 participants) one to three times, and most of the subjects (29) were hallucinogen-naïve (Supplementary Table S1). We performed urine drug tests at screening and before each test session, and no substances were detected during the study.

Study Procedures

Each study included a screening visit, a psychiatric interview, two 25-h experimental sessions, and an end-of-study visit. The experimental sessions were conducted in a quiet standard hospital patient room. The participants were resting in hospital beds except when going to the restroom. Only one research subject and one investigator were present during the experimental sessions. Participants could interact with the investigator, rest quietly and/or listen to music via headphones, but no other entertainment was provided. LSD or placebo was administered at 0900 hours. The subjects were never alone during the first 12 h after drug administration, and the investigator was in a room next to the subject for up to 24 h while subjects were asleep (mostly from 0100 to 0800 hours). Because subjective responses to LSD are pronounced and peak at 2–3 h and last up to 12 h (Passie et al, 2008; Schmid et al, 2015), effects on emotion processing and prosociality were assessed 5 and 7 h after the 100 and 200 μg doses, respectively, when the subjective effects of LSD amounted to approximately 50% of the peak responses (Dolder et al, 2015b; Schmid et al, 2015).

Study Drug

LSD (D-LSD hydrate; Lipomed AG, Arlesheim, Switzerland) was administered in single oral doses of 100 or 200 μg. Both doses are within the range of doses that are taken for recreational purposes (Passie et al, 2008).

Measures

Facial Emotion Recognition Task

We used the FERT, which is sensitive to the effects of other psychoactive substances, including serotonin and norepinephrine uptake inhibitors (Harmer et al, 2004), MDMA (Bedi et al, 2010; Hysek et al, 2014b; Kirkpatrick et al, 2014; Schmid et al, 2014), and methylphenidate (Hysek et al, 2014b; Schmid et al, 2014). The task included 10 neutral faces and 160 faces that expressed one of four basic emotions (ie, happiness, sadness, anger, and fear), with pictures morphed between 0% (neutral) and 100% in 10% steps. Two female and two male pictures were used for each of the four emotions. The stimuli were presented in random order for 500 ms and then were replaced by the rating screen where participants had to indicate the correct emotion. The outcome measure was accuracy (proportion correct). The FERT was performed 5 and 7 h after the 100 and 200 μg doses of LSD, respectively.

Multifaceted Empathy Test

The MET is a reliable and valid task that assesses the cognitive and emotional aspects of empathy (Dziobek et al, 2008). The MET has been shown to be sensitive to oxytocin (Hurlemann et al, 2010), MDMA (Hysek et al, 2014a; Kuypers et al, 2014; Schmid et al, 2014), and psilocybin (Preller et al, 2015). The computer-assisted test consisted of 40 photographs that showed people in emotionally charged situations. To assess cognitive empathy, the participants were required to infer the mental state of the subject in each scene and indicate the correct mental state from a list of four responses. Cognitive empathy was defined as the percentage of correct responses relative to total responses. To measure emotional empathy, the subjects were asked to rate how much they were feeling for an individual in each scene (ie, explicit emotional empathy) and how much they were aroused by each scene (ie, implicit emotional empathy) on a 1–9 point scale. The latter rating provides an inherent additional assessment of emotional empathy, which is considered to reduce the likelihood of socially desirable answers. The three aspects of empathy were each tested with 20 stimuli with positive valence and 20 stimuli with negative valence, resulting in a total of 120 trials. The MET was performed 5 h and 30 min after the 100 μg LSD dose and 7 h and 30 min after the 200 μg LSD, respectively.

SVO test

We used the paper version of the validated SVO test to assess social behavior (Murphy et al, 2011). The SVO measure was previously shown to be sensitive to MDMA (Hysek et al, 2014a). In this economic resource allocation task, prosociality is defined as behavior that maximizes the sum of resources for the self and others and minimizes the difference between the two. The test consists of six primary and nine secondary SVO slider items with a resource allocation choice over a defined continuum of joint payoffs (Murphy et al, 2011). The participants were instructed to choose a resource allocation that defined their most preferred joint distribution between themselves and another person. The allocated funds had real value, and four randomly selected subjects received the funds they earned. Mean allocations for the self and the other were calculated (Hysek et al, 2014a; Murphy et al, 2011), and the inverse tangent of the ratio of these two means produced an angle that indicated the participants’ SVO index. A smaller SVO angle indicates more individualistic or competitive behavior, and a larger SVO angle indicates more prosocial or even altruistic behavior. The SVO was performed 6 and 8 h after the 100 and 200 μg doses of LSD, respectively.

Subjective mood

The VASs and the AMRS (Janke and Debus, 1978) were repeatedly used to assess subjective effects including aspects of empathy and sociality (Hysek et al, 2014a; Schmid et al, 2015) (Supplementary Material and Methods).

Vital signs and adverse effects

Blood pressure, heart rate, body temperature, pupil diameter, and adverse effects were measured as described in the Supplementary Material and Methods.

Drug concentrations

Blood samples for the analysis of plasma LSD levels were collected in lithium heparin tubes after completing the social cognitive tests 6 and 8 h after administration of the 100 and 200 μg doses of LSD or placebo, respectively. Plasma LSD concentrations were determined using liquid-chromatography tandem mass spectrometry (Dolder et al, 2015a).

Statistical Analyses

All of the data were analyzed using repeated measures analysis of variance (ANOVA), with drug (LSD vs placebo) as the within-subjects factor and dose (100 vs 200 μg) as the between-subjects factor, followed by the Tukey’s post hoc test based on significant main effects or interactions. Repeated subjective measures were expressed as peak effects prior to the ANOVAs. Additionally, differences at individual time points were also compared using paired t-tests. Modulatory effects by sex or previous hallucinogen use were excluded by adding sex or substance use as an additional factor to the ANOVAs. Sex or previous substance use did not moderate outcome measures.