The paradoxical psychological effects of lysergic acid diethylamide (LSD), R. L. Carhart-Harris et al., 2016

The paradoxical psychological effects of lysergic acid diethylamide (LSD)

R. L. Carhart-Harris, M. Kaelen, M. Bolstridge, T. M. Williams, L. T. Williams, R. Underwood, A. Feilding and D. J. Nutt

Psychological Medicine, 2016, 46, 1379–1390.



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.

Key words : LSD, mood, psychedelics, psychosis, serotonin.



Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or ‘psychedelic’ that alters consciousness in a marked and unusual way. The drug was first intentionally consumed by the Swiss chemist Albert Hofmann in 1943 in a self-experiment in which he ingested 250 μg (a high dose) in his laboratory before travelling home. In a detailed report of his experience, written a few days later, Hofmann describes an initially unpleasant experience, characterized by altered perception, fear and paranoia: his next-door neighbour transformed into a ‘malevolent, insidious witch with a coloured mask’, he sensed a ‘disintegration of the outer world’, a ‘dissolution of [his] ego’ and was ‘seized by a dreadful fear of going insane’ (Hofmann, 1980).

From this account, it would be reasonable to suspect that Dr Hofmann was negatively affected by this experience but his description of his mental state the next day suggests otherwise: ‘I then slept, to awake the next morning with a clear head. . . A sensation of wellbeing and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created.’(Hofmann, 1980)

When LSD was first distributed by Sandoz pharmaceuticals in 1948, product guidelines stipulated two
main applications: (1) analytical psychotherapy and (2) experimental studies on psychoses. The rationale for the former was that LSD could ‘elicit [the] release of repressed material and provide mental relaxation for anxiety and obsessional neuroses’, and, for the latter, that it could model aspects of psychosis and facilitate an understanding of its nature and pathogenesis (Hofmann, 1980). These two properties formed the basis of a large number of research projects with LSD in the 1950s and 1960s. However, the apparent paradox by which the same compound can be both a model of, and yet a treatment for, psychopathology has never been properly addressed.

In the early years of research with LSD, its remarkable potency (LSD is psychoactive in doses of 25 μg
or lower; Hintzen & Passie, 2010) led psychiatrists to speculate about the existence of an endogenous
LSD-like ‘schizotoxin’ in the brains of patients with schizophrenia (Osmond & Smythies, 1952). In subsequent years, however, focus shifted more onto therapeutic applications, such as treating alcohol
dependence, mood disorders and anxiety related to dying. Human research with LSD was brought to a
halt in the late 1960s due to political pressure, motivated in part by reports of adverse psychological reactions among people using the drug improperly. Ironically, however, at the same time, reports of therapeutic success in the treatment of various psychiatric disorders were beginning to amount (Grinspoon & Bakalar, 1979). In the last 18 months, five new reports on clinical research with LSD have appeared in the scientific press (Carhart-Harris et al. 2014a; Gasser et al. 2014; Schmid et al. 2014; Dolder et al. 2015; Kaelen et al. 2015), one of which focused on the drug’s therapeutic effects (Gasser et al. 2014) and, another, its psychotomimetic effects (Schmid et al. 2014).

Clinical research with psychedelics is currently undergoing a major revival and modern studies are
documenting the same paradoxical properties that were historically described with LSD. For example, in a controlled study in healthy volunteers, high-dose psilocybin produced strong or extreme fear in 30% of
healthy volunteers and yet 80% reported improvements in wellbeing after the experience, with none
reporting any decreases (Griffiths et al. 2006). Remarkably, in follow-up of the same sample, 65%
reported improved wellbeing 14 months after their (single) psilocybin experience (Griffiths et al. 2008) and significant increases in the personality trait openness were also evident (MacLean et al. 2011). These finding in healthy volunteers are supplemented by an increasing number of patient studies. Clinical improvements have been observed with psilocybin-assisted psychotherapy for the treatment of tobacco (Johnson et al. 2014) and alcohol addiction (Bogenschutz et al. 2015), obsessive–compulsive disorder (Moreno et al. 2006) and anxiety related to dying (Grob et al. 2011). Many of these reports mention some 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 (Reich & Hepps, 1972). However, such cases are rare and largely restricted to recreational use. Evidence does not support the view that psychedelics are harmful to mental health (Hendricks et al. 2015). Indeed, to the contrary, two recent population studies found decreased rates of suicidality and psychological distress among persons reporting previous use of psychedelics (Hendricks et al. 2015) and no evidence of any increased rates of mental health problems (Krebs & Johansen, 2013). Similarly, large meta-analyses of controlled research have found that cases of mental health complications following exposure to a psychedelic are extremely rare (i.e. <0.1%), even in vulnerable populations (i.e. <0.2%), and are rarer still if volunteers are properly screened (Cohen & Ditman, 1962; Studerus et al. 2011).

The main aim of the present study was to investigate the acute and ‘mid-term’ (i.e. 2 weeks after the acute experience) psychological effects of LSD in a placebocontrolled study in healthy volunteers. Validated measures of personality, optimism and psychotic symptoms were collected at baseline and 2 weeks post-LSD/placebo and measures of mood, cognition and psychotomimetic states were collected at the end of each dosing day. It was predicted that LSD would induce emotional lability and psychosis-like symptoms acutely but increase psychological wellbeing and openness in the longer term.