Modern Clinical Research on LSD

Abstract

All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT_2A receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility. LSD impaired the recognition of sad and fearful faces, reduced left amygdala reactivity to fearful faces, and enhanced emotional empathy. LSD increased the emotional response to music and the meaning of music. LSD acutely produced deficits in sensorimotor gating, similar to observations in schizophrenia. LSD had weak autonomic stimulant effects and elevated plasma cortisol, prolactin, and oxytocin levels. Resting-state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated. LSD increased functional thalamocortical connectivity and functional connectivity of the primary visual cortex with other brain areas. The latter effect was correlated with subjective hallucinations. LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 days later. In patients with anxiety associated with life-threatening disease, anxiety was reduced for 2 months after two doses of LSD. In medical settings, no complications of LSD administration were observed. These data should contribute to further investigations of the therapeutic potential of LSD in psychiatry.

Figure 1

Effects of LSD on the 5D-ASC scale. The data are derived from three studies using doses of 75 μg i.v. (Carhart-Harris et al, 2016b), 100 μg p.o. (Liechti et al, 2017), and 200 μg p.o. (Schmid et al, 2015) LSD in healthy subjects. LSD predominantly increased ratings in subscales of the dimensions oceanic boundlessness and visionary restructuralization. LSD-induced increases in subscales of the anxious ego-dissolution dimension and in particular in the anxiety scale were relatively small. LSD-induced changes on the 5D-ASC scale were significant compared with placebo for all LSD doses and all of the scales, with the exception of the effects of the 200 μg dose on anxiety. There were no statistical differences in the effects of the intravenous 75 μg (Carhart-Harris et al, 2016b) and oral 100 μg (Liechti et al, 2017) dose of LSD on 5D-ASC scale ratings (data provided by the authors). At 200 μg, LSD produced significant and relevantly higher ratings of blissful state, insightfulness, and changed meaning of percepts compared with 100 μg. The data are expressed as the mean in 24, 16, and 20 subjects for the 100 μg, 200 μg, and 75 μg doses of LSD, respectively.

Figure 2

(a) Mean percentage differences (+SEM) in CBF (red), integrity (blue), and signal variance (green) in 12 different resting-state networks (RSNs) under LSD relative to placebo (red asterisks indicate statistical significance, *P<0.05; **P<0.01, Bonferroni corrected). (b) Differences in between-RSN RSFC or RSN ‘segregation’ under LSD vs placebo. Each square in the matrix represents the strength of functional connectivity (positive=red, negative=blue) between a pair of different RSNs (parameter estimate values). The matrix on the far right displays the between-condition differences in covariance (t values): red=reduced segregation and blue=increased segregation under LSD. White asterisks represent significant differences (P<0.05, FDR corrected; n=15). Reproduced from Carhart-Harris et al (2016c).

Figure 3

Connectome ring showing functional connectivity between 132 regions covering the whole brain. Contrast LSD vs placebo, P<0.05, FDR. Yellow-red indicates increased functional connectivity, blue indicates decreased connectivity. Figure provided by F Mueller from the Basel fMRI study (Mueller et al, 2017b).

Figure 4

Pharmacokinetics and pharmacodynamics of LSD. LSD concentration-time (a) and subjective effect-time (b) curves. LSD was administered at a dose of 100 and 200 μg p.o. to 24 and 16 healthy subjects, respectively, at the time point t=0. Subjective LSD effects (‘any subjective drug effects’) were assessed repeatedly using VASs (0–100%) along with blood samples to determine plasma concentrations of LSD (Dolder et al, 2015b; Dolder et al, 2016; Dolder et al, 2017). The LSD concentration curves (a) represent the mean±SEM of the individual curves fitted to the observed data using a 1-compartment model. The subjective drug effect curves (b) represent the mean±SEM of the individual curves fitted to the observed data using a sigmoidal E_max model linked to the predicted concentrations (Dolder et al, 2017).