Acute effects of lysergic acid diethylamide in healthy subjects

This double-blind, placebo-controlled study (n=16) described the effects of LSD (200 μg) in healthy subjects. It inhibited prepulse inhibition (startle reflex), increased blood pressure, elicited a positive mood, and had no adverse effect after 72 hours.

Abstract

“Background: After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.

Methods: In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.

Results: Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.

Conclusions: In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.”

Authors: Yasmin Schmid, Florian Enzler, Peter Gasser, Eric Grouzmann, Katrin H. Preller, Franz X. Vollenweider, Rudolf Brenneisen, Felix Müller, Stefan Borgwardt & Matthias E. Liechti

Notes

This paper is included in the meta-analytical review by Galvão-Coelho and colleagues (2021) that found psychedelics to improve mood (for those with mood disorders) both in the short and long-term (up to 60 days).

A further analysis of the pharmacokinetics/dynamics is done in Dolder and colleagues (2017).

Summary

After 40 years, there is renewed interest in using lysergic acid diethylamide in clinical psychiatric research and practice. However, no modern studies have been conducted on its subjective and autonomic effects. LSD produced pronounced alterations in waking consciousness, visual hallucinations, audio-visual synesthesia, positively experienced derealization and depersonalization phenomena, increased subjective well-being, happiness, closeness to others, openness, and trust, and decreased PPI compared with placebo. LSD produced adverse effects that completely subsided within 72h.

Lysergic acid diethylamide (LSD) is a prototypical classic hallucinogen that was discovered in 1943 by Albert Hofmann in Basel. LSD is illicitly used for recreational (personal or spiritual) purposes. Despite LSD’s widespread recreational use, no scientific pharmacological studies have been conducted with LSD in the last 40 years. We performed a reexamination of the acute response to LSD in healthy subjects using psychometric instruments that have been used with other psychotropic drugs, including hallucinogens, empathogens, and stimulants. Serotonergic hallucinogens, including psilocybin, DMT, and LSD, induce visual perceptual disturbances and alterations in information processing that are similar to those observed in early schizophrenia.

LSD, a hallucinogen, acutely disrupts prepulse inhibition in animals, and therefore serves as a preclinical model of schizophrenia. However, the effects of LSD on sensorimotor gating function have not yet been explored in humans.

We recruited 16 healthy subjects who provided written informed consent and were paid for their participation. Seven subjects had used a hallucinogen 1-3 times and another four subjects had prior experience with MDMA (2-4 times).

A double-blind, placebo-controlled, cross-over design was used with two experimental test sessions in balanced order. The administration of LSD to healthy subjects was authorized by the Swiss Federal Office for Public Health.

LSD was administered in a single absolute dose of 200g, which was within the range of doses taken for recreational purposes.

The study included a screening visit, psychiatric interview, two 25h test sessions, and an end-of-study visit. The subjects were under constant supervision by the study physician until 1:00 AM, and were sent home the next day at 9:30 AM.

Subjective drug effects were assessed using the 5D-ASC, VASs, AMRS, and ARCI. The procedures are described in detail in Supplement 1.

Acoustic startle response was measured using an electromyographic startle system. The system included 16 pulse-alone stimuli and 32 similar pulse trials preceded by a 20ms prepulse.

Data were analyzed using Statistica 12 software. Repeated-measures analysis of variance was used to determine drug effects, and Modulatory effects of sex and hallucinogen experience were evaluated using Spearman’s rank correlations.

Subjective effects on the VASs were moderately increased by LSD, with peak effects occurring 30-60min after LSD administration. The subjective effects were most strongly increased by oceanic boundlessness and visionary restructuralization, with minimal effects occurring on audio-visual synesthesia or changed meaning of percepts.

Subjective effects of LSD were pronounced, lasting up to 12h, and included increases in “any drug effects”, “good drug effect”, “drug high”, “drug liking” and “stimulated”. LSD decreased subjective concentration, and induced small but significant increases in “bad drug effect” and “fear”. LSD significantly increased ratings of well-being, emotional excitation, inactivity, introversion, and dreaminess on the AMRS and ARCI compared with placebo, and did not alter ratings of extroversion or anxiety. No sex differences were observed in the effects of LSD on the ARCI. LSD increased investigator ratings of “any drug effect”, “distance from reality”, “happiness”, and “non-speech vocalization”. LSD did not significantly increase ratings for “anxiety” or “paranoid thinking”.

LSD reduced PPI and startle response habituation in the 30ms, 60ms, and 120ms trial conditions, and also tended to increase the startle response compared with placebo. No associations were found between %PPI disruption and any subjective effect ratings assessed shortly before or after the startle measurement.

LSD significantly increased blood pressure, heart rate, body temperature, pupil size, cortisol, prolactin, oxytocin, and epinephrine in participants compared with placebo, but not adverse effects at 24-72h. There were no severe acute effects.

LSD produced a pronounced alteration in waking consciousness, including visual perceptual alterations, audio-visual synesthesia, and positively experienced derealization and depersonalization. LSD produced high ratings of good drug effects and low ratings of bad drug effects, and lasted 12h in most subjects.

LSD produced similar ratings to high-dose psilocybin on the AMRS and ARCI, and increased ratings on the amphetamine group scale and morphine-benzedrine group scale, suggesting stimulant and euphoric subjective effects similar to MDMA. LSD produced stronger perceptual alterations than other psychotropic drugs tested so far, and also MDMA-like empathogenic mood effects. Additionally, LSD increased plasma oxytocin levels, suggesting that it may be associated with common serotonergic and/or oxytocinergic properties. In laboratory studies, moderate anticipatory anxiety is common with hallucinogens, and acute anxiety was infrequently reported when LSD was administered in patients with anxiety associated with life-threatening diseases.

Two subjects experienced anxiety, which resolved spontaneously with verbal support from the investigators. All subjects had no history of major psychiatric disorders, and were well-informed about the setting, acquainted with and constantly supervised by the same investigator.

LSD disrupted PPI and therefore produced sensorimotor deficits similar to those observed in schizophrenia. Psilocybin increased PPI at long ISIs without changing startle reactivity or habituation, and DMT had no effects on PPI, startle reactivity, or habituation in humans.

LSD disrupts PPI in normal humans, which is consistent with the PPI deficits after LSD administration in animals and sensorimotor gating deficits in schizophrenia patients. Further studies should investigate the effects of receptor antagonists on the response to LSD using a similar experimental setting.

LSD produced sympathomimetic effects including increases in blood pressure, heart rate, and pupil size. LSD increased body temperature, and epinephrine levels were similar to those produced by MDMA.

LSD increased circulating levels of cortisol and prolactin in the present study. This suggests that the serotonergic stimulant effects of LSD on prolactin regulation usurp any dopamine D 2 receptor-mediated inhibition in humans at the dose used in the present study.

We used a relatively high dose of LSD (200 g) to produce a full and representative LSD response, but we cannot provide dose-response data. Additionally, expectations may have influenced the psychological effects of LSD, and endocrine measures were performed only at two time-points during the expected peak drug effect.

LSD may be useful for further studying alterations in consciousness and information processing in humans, but should be used with caution in patients with hypertension or heart disease.

LSD increased ratings of oceanic boundlessness (OB), visionary restructuralization (VR), and auditory alterations (AA) but not anxious ego-dissolution (AED). Vigilance (VIR) was significantly reduced by LSD compared with placebo.

LSD produced significant changes in all VAS ratings, except for “bad drug effects” and “fear”. LSD also increased ratings that are typically increased by empathogens, including ratings for “happy”, “closeness”, “open” and “trust”.

Figure 3 shows that LSD increased general well-being, emotional excitation, inactivity, introversion, and dreaminess, but did not induce significant anxiety.

LSD reduced the percentage of prepulse inhibition of the acoustic startle response in trials with 30 or 60ms prepulses compared with placebo, but did not significantly alter the startle response or startle response habituation.

LSD significantly increased blood pressure, heart rate, and body temperature compared with placebo, and these effects remained significant up to 5 h after drug administration.

LSD significantly increased the levels of several hormones, including prolactin, cortisol, oxytocin, and epinephrine, in the blood of test subjects.