LSD acutely impairs fear recognition and enhances emotional empathy and sociality

The report pooled data from two similar double-blind, placebo-controlled, random-order, crossover studies. Study 1 administered 100 μg oral LSD to 24 healthy participants and Study 2 administered 200 μg to 16 different healthy participants; each participant completed two 25-hour experimental sessions (LSD and placebo) with washout periods of at least 7 days. The studies were approved by the local ethics committee, authorised by Swiss authorities and registered on ClinicalTrials.gov. All participants provided written consent and were paid. Forty healthy volunteers (20 men, 20 women), aged 25–60 years, were recruited. Inclusion/exclusion criteria excluded those younger than 25, older than 65, pregnant women, people with a personal or first-degree family history of major psychiatric disorders, certain medical conditions or medication use, heavy smokers (>10 cigarettes/day), and those with substantial illicit drug histories or recent use; urine drug screening was performed at screening and before each session. Most participants were hallucinogen-naive or had very limited prior hallucinogen experience (1–3 lifetime uses in a minority). Sessions were conducted in a quiet hospital room with one investigator present. LSD or placebo was given at 09:00 and tests of social cognition were scheduled after the peak subjective effects, at a time when participants were in a later ‘plateau’ phase: the FERT was done 5 h after 100 μg and 7 h after 200 μg, the MET at 5.5 h and 7.5 h, and the SVO at 6 h and 8 h, respectively. Blood for plasma LSD was sampled immediately after the social cognitive tests (6 h for 100 μg; 8 h for 200 μg). Primary measures: the FERT presented morphed faces (neutral to 100% in 10% steps) expressing happiness, sadness, anger or fear; outcome was accuracy (proportion correct). The MET assessed cognitive empathy (percent correct inference of mental state) and emotional empathy (explicit feeling-for-other ratings and implicit arousal ratings on 1–9 scales) with 40 photographs (20 positive, 20 negative). The SVO paper slider task measured resource-allocation preferences; mean allocations to self and other produced an angle (SVO index) where larger angles indicate more prosocial orientation. Subjective mood was assessed with Visual Analog Scales (VASs) and the Adjective Mood Rating Scale (AMRS); vital signs and adverse events were recorded. Plasma LSD was quantified by liquid-chromatography tandem mass spectrometry. Analyses used repeated-measures ANOVA with drug (LSD vs placebo) as a within-subject factor and dose (100 vs 200 μg) as a between-subjects factor, followed by Tukey post hoc tests as appropriate. Peak values for repeated subjective measures were used in ANOVAs; paired t-tests compared individual time points. Sex and prior hallucinogen use were tested as potential moderators by inclusion as factors; they did not moderate outcomes. Correlations were examined with Spearman rank tests. The extracted text notes some missing task data for 2 participants in the 100 μg group due to technical problems.

Facial emotion recognition: LSD impaired recognition of fearful faces with a robust main effect of drug (F1,36 = 20.71, p < 0.001); both 100 μg and 200 μg groups showed impairments versus placebo (post hoc p < 0.01 and p < 0.05, respectively). There was also a main effect indicating impaired recognition of sad faces (F1,36 = 7.36, p = 0.01), although post hoc comparisons of each dose with placebo did not reach significance. No significant effects were reported for neutral, happy or angry expressions. Empathy (MET): LSD increased both explicit and implicit emotional empathy (explicit: F1,36 = 14.05, p < 0.001; implicit: F1,36 = 6.71, p = 0.01). Post hoc tests showed that the 200 μg dose produced significant increases in explicit (p < 0.01) and implicit (p = 0.01) empathy versus placebo, whereas the 100 μg dose did not. Valence-specific analyses indicated that LSD significantly increased explicit and implicit empathy for positive stimuli (explicit: F1,36 = 24.32, p < 0.001; implicit: F1,36 = 10.47, p < 0.01) with only trend-level effects for negative stimuli. In contrast, cognitive empathy decreased under LSD (F1,36 = 16.87, p < 0.001), and post hoc tests showed this reduction was significant for both 100 μg and 200 μg doses compared with their respective placebo conditions (both p < 0.05). Social value orientation: There was a significant main effect of drug on the SVO angle (F1,38 = 4.31, p < 0.05), indicating an overall shift toward greater prosociality under LSD in the pooled sample. However, this effect did not reach significance within the individual dose groups when examined separately. Subjective mood and correlations: LSD increased maximal VAS ratings for items reflecting empathy and prosociality (for example, ‘feeling close to others’, ‘open’, ‘trust’, and ‘I want to be with others’), with larger peak effects at 200 μg; ratings of ‘happy’ rose similarly at both doses. Small dose-dependent increases occurred for ‘bad drug effect’ and ‘fear’. On the AMRS, LSD increased scores for ‘well-being’, ‘emotional excitation’, ‘inactivity’, ‘introversion’, and ‘dreaminess’. Plasma LSD concentrations were 0.7 ± 0.3 ng/ml at 6 h after 100 μg and 1.3 ± 0.6 ng/ml at 8 h after 200 μg. Plasma levels correlated with explicit emotional empathy for positive stimuli (Spearman s = 0.37, p < 0.05) and with LSD-induced ratings of trust (s = 0.32, p < 0.05). VAS ratings of ‘closeness’ and ‘trust’ correlated with greater explicit empathy for positive stimuli (s = 0.35, p < 0.05 and s = 0.47, p < 0.01, respectively). Vital signs and adverse effects: Both doses produced moderate sympathomimetic effects—elevated blood pressure, heart rate, body temperature and pupil dilation—with no drug × dose interaction. Acute adverse effects (0–10 h) increased for both doses; only the high dose increased subacute adverse effects (10–24 h). Adverse effects at 24–72 h were slightly increased in the pooled sample but not within the separate studies. Commonly reported adverse events included dizziness, headache and fatigue; no severe adverse events occurred. The extracted text notes that sex and prior hallucinogen use did not moderate the outcomes.

Dolder and colleagues interpret their results as showing that LSD acutely alters emotional processing by reducing recognition of negative facial emotions (fear and, to a lesser extent, sadness), while enhancing emotional empathy and prosocial orientation. The pattern observed—impaired detection of negative emotions together with increased explicit and implicit empathy particularly for positive stimuli—resembles effects previously reported for MDMA and, to some extent, for psilocybin. The investigators note that LSD produced both empathogenic subjective effects (feelings of closeness, trust, desire to be with others, happiness and openness) and psychedelic peak effects, and that these empathogenic effects persisted into a later ‘‘plateau’’ phase (approximately 6–12 h) when testing was conducted and participants were less overwhelmed by peak alterations in consciousness. In contrast to MDMA, LSD also reduced cognitive empathy on the MET and, at the higher dose, produced some nonspecific performance decrements (for example, decreased recognition of neutral faces), which the authors acknowledge as possibly reflecting generalised effects on attention or motivation. The authors suggest that the later-phase emotional and social effects of LSD may be favourable for facilitating a therapeutic alliance in LSD-assisted psychotherapy, but they emphasise that future work should disentangle the therapeutic contributions of the psychedelic ‘‘peak’’ versus the empathogenic emotional effects. The study's tolerability is described as acceptable in a controlled setting; physiological activation and transient adverse effects were moderate and no serious adverse events occurred. The authors list several limitations: dose groups were studied between participants rather than within-subjects; the tests employed artificial pictorial stimuli rather than real interpersonal interactions; face-muscle responses or measures of being cared-for were not assessed; and task performance could have been influenced by attention or motivation rather than specific emotion-processing changes. They call for replication and extension using additional emotion recognition measures, response measures and social interaction paradigms to clarify the findings and their clinical relevance. Overall, the authors conclude that a single administration of LSD can both reduce perception of negative emotions and increase emotional empathy and prosocial behaviour in healthy volunteers, effects they consider potentially translational to LSD-assisted psychotherapy, while urging caution due to the noted limitations.