The paradoxical psychological effects of lysergic acid diethylamide (LSD)

This double-blind, placebo-controlled study (n=20) found that LSD (75µg) acutely heightened mood and psychosis-like symptoms. At the two-week follow-up, participants reported increased optimism and openness.

Abstract

“Background: Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.

Method: A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter’s Delusions Inventory were issued at baseline and 2 weeks after each session.

Results: LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.

Conclusions: The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of ‘loosened cognition’ in the mid to long term that is conducive to improved psychological wellbeing.”

Authors: Robin L. Carhart-Harris, Mendel Kaelen, Mark Bolstridge, Tim M. Williams, Luke T. Williams, Raphael Underwood, Amanda Feilding & David J. Nutt

Notes

This study was funded in part by the Beckley Foundation.

This study used the same participants as Tagliazucchi et al. (2016), which looked at the fMRI scans (of which they could use 15 of the 20 participants’ data).

As with other studies (e.g. MacLean et al. (2011), which found an increase in trait openness), the optimism scores were changed quite a bit more (d – effect size – = 0.56) than openness (d = 0.16). Psychedelics may indeed lead to a change in personality, but this is a much smaller effect than it has on other measures.

Summary

Introduction

LSD is a potent serotonergic hallucinogen that alters consciousness in a marked and unusual way. It was first intentionally consumed by the Swiss chemist Albert Hofmann in 1943 in a self-experiment.

Dr Hofmann’s description of his mental state the next day suggests that he was not negatively affected by this experience.

LSD was first distributed in 1948 and was used for analytical psychotherapy and experimental studies on psychoses. However, the compound can be both a model of and a treatment for psychopathology.

In the early years of research with LSD, its remarkable potency led psychiatrists to speculate about the existence of an endogenous LSD-like ‘schizotoxin’ in the brains of patients with schizophrenia. However, in subsequent years, focus shifted more towards therapeutic applications, such as treating alcohol dependence, mood disorders and anxiety related to dying.

Clinical research with psychedelics is currently undergoing a major revival, with many reports mentioning psychological discomfort during the acute experience, yet the therapeutic benefits have been impressive and enduring.

Case reports of persistent psychological problems apparently precipitated by a psychedelic have considerable potential to excite alarm. However, evidence does not support the view that psychedelics are harmful to mental health.

The present study investigated the acute and mid-term psychological effects of LSD in healthy volunteers. It was predicted that LSD would induce emotional lability and psychosis-like symptoms acutely.

Experimental design

This was a placebo-controlled, within-subjects/crossover study with a balanced-order design, in which 20 healthy volunteers were recruited via word of mouth and made three study visits: screening, dosing session 1 and dosing session 2.

Volunteers were blind to the dosing order, but the research team was not, and subjective ratings were completed electronically and remotely soon after screening and 2 weeks after a dosing session.

Screening

Prior to study enrolment, volunteers attended a screening visit at the Imperial Clinical Research Facility at the Hammersmith Hospital in West London. They were screened for physical and mental health, and were asked to refrain from using other recreational drugs for the duration of the study.

Study procedures

Participants were asked to arrive at the study centre at or before 09.00 hours and gave a urine test for drugs of abuse and pregnancy. They were infused with LSD or a placebo solution over 2 min.

After dosing, volunteers completed a functional neuroimaging protocol, which included a mock MRI scanner, a real MRI scanner, a magnetoencephalography (MEG) scanner, a structured interview, and a battery of cognitive and behavioural tests.

LSD was infused into participants’ veins and the effects peaked approximately 120 min post-infusion. Participants were discharged when they were considered to be functioning normally.

Acute outcomes

Participants completed two questionnaires at the end of each study day, one about the subjective experience of LSD and the other about how they generally felt throughout the day.

Mid-term outcomes

The Revised Life Orientation Test, the Revised NEO Personality Inventory and the Peters’ Delusions Inventory were used to assess mid-term effects of psychedelic use.

Data analysis

Repeated-measures analyses of variance were used to test for differences between conditions in the ASC, PSI and PDI, and paired t tests were used to analyse changes in the LOT-R. To test for order confounds, participants’ order was included in significant tests.

Participants

A total of 20 healthy volunteers participated in the study. They had at least one previous experience with a classic psychedelic drug, and self-estimated their current drug use as follows: 10.3 weekly alcohol units, 0.3 daily cigarettes, 705 cannabis uses, 27 MDMA uses, 3.6 ketamine uses, and 9.6 cocaine uses.

Acute subjective effects of LSD

A repeated-measures ANOVA revealed that the LSD experience was dominated by changes in visual perception, but that all 11 dimensions of the ASC were significantly higher after LSD than placebo.

A repeated-measures ANOVA revealed that the condition had a significant effect on the psychosis severity index (PSI) and that the condition had a significant effect on the PSI’s factors other than anhedonia.

Mid-term subjective effects of LSD

Optimism and openness were increased 2 weeks after LSD, but there were no such changes post-placebo. There was a trend towards an increase in trait agreeableness post-LSD, however, this did not survive correction for multiple comparisons.

Repeated-measures ANOVA found no change in delusional thinking 2 weeks after LSD, but exploratory t tests suggested a trend towards less distress and less preoccupation with ‘delusional thoughts’.

Predictors of the mid-term effects of LSD

Regarding baseline predictors of the mid-term effects of LSD, correlations were found between baseline agreeableness, depression and anxiety and increases in openness, but none survived correction for multiple comparisons.

There was a negative correlation between acute anxiety and post-LSD increases in optimism, and a positive correlation between impaired/disorganized cognition and post-LSD increases in openness, but these correlations failed to survive correction for multiple comparisons.

Discussion

In a controlled study, LSD increased emotional lability and psychosis-like symptoms acutely, and optimism and openness 2 weeks later.

LSD is a potent psychotomimetic, with scores on the PSI confirming this view. Only cannabis in highly schizotypal individuals produces scores of an equivalent magnitude to those seen here with LSD.

LSD produced relatively strong subjective effects as indexed by the ASC, which were similar to those produced by psilocybin, MDMA and ketamine.

With the PSI results in mind, it is worth briefly discussing the relative merits of different drug models of psychosis. Ketamine is often described as an especially meritorious model of psychosis, but the premise that negative symptoms can be modelled by an acute drug state is questionable.

Based on the PSI results, one might infer that participants’ acute LSD experiences were dominated by unpleasant psychosis-like phenomena, but this was not the case. Instead, positive mood was more common, and some volunteers showed frank psychotic phenomena.

The findings that optimism and openness are increased 2 weeks after LSD are consistent with previous findings that psychedelics can improve psychological well-being and increase openness. These findings are also consistent with the notion that psychedelics may have therapeutic potential in the treatment of depression.

The present study had several limitations, including a short follow-up period, a single-blind design, and MRI and MEG scans that each lasted for over 60 min. However, the high PSI scores observed with LSD may be due to the combination of drug plus scanner.

The serotonin 2A receptor (5-HT2AR) is central to the psychopharmacology of psychedelics, and the stimulation of the 5-HT2AR promotes certain aspects of learning and cognition, including flexibility of cognition. This may explain why positive mood and flexible, creative thinking are associated with psychedelics.

Psychedelics impair certain aspects of cognition, including the ability to focus and concentrate. 5-HT2AR antagonism attenuates the positive mood effects of psilocybin and MDMA, but also attenuates the positive psychotic symptoms.

The psychedelic state has been characterized as an ‘entropic’ state, in which the mind/brain operates outside of its normal, optimal level of order, in a realm of relative disorder. This may explain why 5-HT2AR stimulation has been associated with both positive and negative facets of the acute psychedelic state.

Valence-specific items such as feeling euphoric or sad would load more heavily onto the first principal component than valence-specific items such as loss of self/ego, loss of ego-boundaries, altered meaning and muddled thinking.

The discussion so far has focused mainly on the paradoxical acute psychological effects of psychedelics. However, the longer-term effects of psychedelics may be more clinically relevant, and may include increased psychological wellbeing, openness, decreased suicidality, and increased optimism. We investigated the paradoxical psychological effects of LSD in healthy volunteers. We predict that deficient 5-HT2AR stimulation causes cognition to ‘stultify’, whereas 5-HT2AR stimulation loosens cognition and associated brain dynamics, serving as a metaphorical ‘lubricant’ for the mind and brain.

Acute psychological effects included psychosis-like symptoms but also positive mood, and no increases in delusional thinking.

Acknowledgements

The research presented in this report was funded by the Beckley Foundation and the Walacea.com crowd-funding campaign.