Acute effects of lysergic acid diethylamide in healthy subjects

Classic serotonergic hallucinogens such as lysergic acid diethylamide (LSD) produce profound alterations of perception and cognition and were widely studied in mid-20th century psychiatry, but modern controlled pharmacological data on LSD in humans are lacking. In particular, contemporary studies have not systematically characterised LSD's subjective, autonomic, and endocrine effects, and the drug's influence on prepulse inhibition (PPI) of the acoustic startle response—a translational measure of sensorimotor gating relevant to schizophrenia—had not been examined in humans. Schmid and colleagues therefore set out to re-examine the acute effects of LSD in healthy volunteers. The study aimed to characterise subjective experiences with validated psychometric instruments, test the hypothesis that LSD impairs PPI, and document cardiovascular, autonomic, endocrine, and adverse effects using a modern, double-blind, placebo-controlled, crossover design.

Sixteen healthy adults (eight men, eight women; mean age 28.6±6.2 years, range 25–51) were enrolled after screening and informed consent. Recruitment was by word of mouth and a university web listing; seven participants had used a hallucinogen 1–3 times and four had prior MDMA experience. The investigators followed contemporary ethical and regulatory procedures and registered the trial (ClinicalTrials.gov NCT01878942). The design was double-blind, randomised, placebo-controlled, crossover with two 25-hour test sessions per subject and washout intervals of at least 7 days. A single absolute oral dose of LSD 200 µg was administered (mean dose 2.84±0.13 µg/kg). Sessions began at 08:15, urine toxicology and pregnancy tests were performed, and the drug or placebo was given at 09:00. Subjects were observed continuously for the first 16 hours and assessed repeatedly for 24 hours; they returned home the following morning. Subjective outcomes included the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale (administered 24 hours retrospectively to capture peak effects), Visual Analogue Scales (VASs) repeatedly up to 24 hours, the Adjective Mood Rating Scale (AMRS) and the Addiction Research Center Inventory (ARCI) at baseline and 3, 10, and 24 hours. Sensorimotor gating was assessed by electromyographic measurement of the eye-blink acoustic startle response, using 16 pulse-alone trials (115 dB) and 32 prepulse trials with a 20 ms prepulse (86 dB) at interstimulus intervals (ISIs) of 30, 60, 120, or 2000 ms. Cardiovascular and autonomic measures included blood pressure, heart rate, body temperature, pupillometry, balance testing and psychomotor performance. Endocrine assays measured plasma cortisol, prolactin, oxytocin, norepinephrine, and epinephrine. Data were analysed in Statistica 12. Peak (Emax) or peak-change (ΔEmax) values were derived for repeated measures and compared with repeated-measures ANOVA with drug (LSD vs placebo) as a within-subjects factor. PPI analyses included drug and trial condition as within-subjects factors; sex and prior hallucinogen experience were included as between-subjects factors where relevant. Spearman correlations explored associations between measures. The threshold for significance was p<.05. One participant's startle data were excluded for technical reasons.

Subjective effects: LSD produced robust alterations of waking consciousness. On the 5D-ASC, LSD strongly increased ratings of oceanic boundlessness (F1,15=92.3, p<.001) and visionary restructuralization (F1,15=243.5, p<.001), including marked increases in elementary and complex imagery, audio-visual synesthesia, and altered meaning of percepts. Ratings indicating positively experienced derealization and depersonalization (for example, "experience of unity" and "blissful state") were elevated, while pronounced anxiety or panic was uncommon; two subjects had transient anxiety that resolved within 2–3 hours with no medication. Peak subjective effects began 30–60 minutes after dosing and occurred at 1.75±0.82 hours; effects remained high for 3–5 hours and lasted up to 12 hours in most subjects, with some reporting effects up to 16 hours. On repeated VASs, LSD produced large increases in "any drug effect," "good drug effect," "drug high," "drug liking," and "stimulated" (peak items reached up to 90% of the maximal score), and selectively increased empathogenic items such as "happy," "closeness," "open," and "trust" (all F1,15 ≥34, p<.001). The AMRS showed increased well-being, emotional excitation, inactivity, introversion, and dreaminess (all p<.05), while the ARCI indicated raised scores on the amphetamine group and morphine–benzedrine group scales and on the LSD group scale. Investigator ratings corroborated increased overall drug effect, distance from reality and happiness; neither investigator nor self-ratings showed increases in paranoid thinking. No consistent sex differences or clear effects of limited prior hallucinogen experience were observed. Acoustic startle and PPI: One participant's startle data were excluded. Repeated-measures ANOVA revealed a significant drug × prepulse condition interaction (F3,42=3.0, p<.05). LSD significantly reduced PPI at the 30 ms and 60 ms ISIs (F1,14=5.5, p<.05 and F1,14=5.1, p<.05, respectively) and showed a trend toward reduction at 120 ms (F1,14=3.4, p=.09). Mean startle amplitude across pulse-alone trials was nonsignificantly higher after LSD (571±321 units) than placebo (469±190 units), and habituation over time was observed similarly in both conditions; LSD did not significantly alter startle habituation. No correlations were found between the magnitude of PPI disruption and concurrent subjective ratings. Cardiovascular, autonomic, endocrine and adverse effects: LSD increased systolic blood pressure (F1,15=23.77, p<.001), diastolic blood pressure (F1,15=25.19, p<.001), heart rate (F1,15=15.27, p=.001) and body temperature (F1,15=11.61, p=.004). Pupillary diameter increased in dark and light conditions (F1,15=22.71 and 36.33, both p<.001), and balance (one-foot test) was impaired (F1,15=26.1, p=.001). Endocrine measures showed marked increases in plasma cortisol (F1,15=198.03, p<.001), prolactin (F1,15=10.13, p<.01), oxytocin (F1,15=9.40, p<.01), and epinephrine (F1,15=8.95, p<.01). Acute (0–10 h) and subacute (10–24 h) adverse effect scores were higher after LSD (F1,15=13.67, p<.01 and F1,15=7.19, p<.05, respectively) but adverse effects at 24–72 h did not differ from placebo; no severe acute adverse events occurred. Somatic and endocrine effects did not differ by sex.

Schmid and colleagues interpret the findings as demonstrating that a single oral dose of LSD 200 µg produces pronounced perceptual alterations and also mood effects that resemble those induced by empathogens such as MDMA. The investigators note that elevated ratings of happiness, closeness and trust, together with increased plasma oxytocin, may underlie the empathogenic subjective profile observed, while LSD's stronger visual and synesthetic phenomena distinguish it from MDMA and align it with other classic serotonergic hallucinogens. The observed reduction in PPI at short and medium ISIs supports preclinical data showing LSD-induced disruption of sensorimotor gating and mirrors PPI deficits reported in schizophrenia, thereby positioning LSD as a human pharmacological model for studying neural mechanisms relevant to psychosis. The authors highlight the likely involvement of 5-HT2A receptor stimulation in both subjective and PPI effects and recommend future studies that probe receptor mechanisms using selective antagonists. Autonomic and endocrine results showed moderate sympathomimetic stimulation, including increases in blood pressure, heart rate, pupil size and epinephrine, and substantial rises in cortisol and prolactin; the pattern is consistent with serotonergic activation and may overshadow any pituitary D2-mediated effects at this dose. The investigators observe that these somatic effects were generally moderate compared with stimulants and empathogens but should be considered when contemplating LSD administration in people with cardiovascular disease or hypertension. The authors acknowledge several limitations: only a single, relatively high dose was tested so no dose–response data are available; blinding was compromised by the overt nature of LSD's effects and subjects knew the two possible conditions (LSD or placebo), which may have influenced expectations; endocrine sampling was limited to two time points during peak effect and therefore cannot fully characterise hormonal time courses; and the healthy, screened, supervised laboratory setting constrains generalisability to recreational contexts or clinical populations. Despite these caveats, the study demonstrates that LSD can be administered safely in a controlled research setting and provides a platform for further psychopharmacological and translational investigations into consciousness, social-emotional processing, and sensorimotor gating.