Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects
Yasmin Schmid, Florian Enzler, Peter Gasser, Eric Grouzmann, Katrin H. Preller, Franz X. Vollenweider, Rudolf Brenneisen, Felix Müller, Stefan Borgwardt, and Matthias E. Liechti
Biological Psychiatry, 2014, Vol. 78, 8, 544-553
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 methylenedioxy-methamphetamine-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.
Keywords : Adverse effects, Hormones, LSD, Prepulse inhibition, Subjective effects, Sympathomimetic effects
Lysergic acid diethylamide (LSD) is a prototypical classic hallucinogen (1,2). The psychotropic effects of LSD were discovered in 1943 by Hofmann in Basel (3). In the 1950s– 1970s, LSD was initially used as an experimental tool (“psychotomimetic”) to study psychotic-like states and model psychosis (4,5) and as an adjunct in “psycholytic psychotherapy.” It has also been investigated for the treatment of alcoholism (6), addiction (7), cluster headache (8), and anxiety associated with terminal illness (9–11). Today, LSD is used illicitly for recreational (personal or spiritual) purposes. The lifetime prevalence of LSD use among adults is 6%–8% (12,13). Despite the widespread recreational use, no experimental scientific pharmacologic studies have been conducted with LSD in the last 40 years, until recently (14). After the initial psychiatric investigation by Stoll (15), several case reports and studies in the 1950s and 1960s described aspects of the psychological effects of LSD (5,16–18). However, these studies were not performed according to current research standards and did not include control conditions or the systematic characterization of psychotropic effects. Many studies also sought to describe the psychotomimetic effects of LSD but were not designed to measure any positive subjective effects. Modern experimental studies with hallucinogens in humans resumed in the 1990s with N-N-dimethyltryptamine (DMT; also known ayahuasca) (19–22), ketamine (22–24), and psilocybin (25,26), but not with LSD. More recently, LSD and psilocybin have been evaluated in pilot therapeutic studies as treatments for anxiety in patients with life-threatening diseases (11,27). Because of the continued popularity of LSD as a recreational drug and renewed interest in its therapeutic use (11,28), we reexamined the acute response to LSD in healthy subjects. To allow for a better characterization of the subjective effects of LSD, we used psychometric instruments that have been used with other psychotropic drugs, including hallucinogens, empathogens, and stimulants (21,22,29–32).
Serotoninergic hallucinogens, including psilocybin, DMT, and LSD, elicit mostly visual perceptual disturbances that resemble perceptual disturbances observed in early schizophrenia (22,33–35). Hallucinogens also induce alterations in information processing that are similar to those observed in schizophrenia. Specifically, prepulse inhibition (PPI) of the acoustic startle response serves as an operational measure of sensorimotor gating that can be assessed in animals and humans (36). In schizophrenia, PPI is impaired in prodromal states and early phases (36–39), and hallucinogens such as
LSD acutely disrupt PPI in animals (40–45). In animals, PPI serves as a preclinical model of schizophrenia (46). The effects of LSD on sensorimotor gating function have not yet been explored in humans and were tested in the present study. We hypothesized that LSD would produce alterations in waking consciousness and impair PPI. Additionally, no data are available on the acute autonomic and adverse effects of LSD, and the endocrine effects of LSD in humans are unknown. Up-to-date clinical safety data are mostly missing. Because of the continued popularity of LSD as a recreational drug and interest in its therapeutic use, we also examined the acute somatic and endocrine response to LSD.