Article

LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality

Abstract

Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.Neuropsychopharmacology accepted article preview online, 01 June 2016. doi:10.1038/npp.2016.82.
OPEN
LSD Acutely Impairs Fear Recognition and Enhances Emotional
Empathy and Sociality
Patrick C Dolder
1
, Yasmin Schmid
1
, Felix Müller
2
, Stefan Borgwardt
2
and Matthias E Liechti*
,1
1
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel,
Basel, Switzerland;
2
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients
with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing
in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion
Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value
Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, crossover studies were conducted using 100 μg LSD
in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers
(20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on
the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participantsdesire to be with other people
and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for
LSD-assisted psychotherapy.
Neuropsychopharmacology (2016) 41, 26382646; doi:10.1038/npp.2016.82; published online 22 June 2016
INTRODUCTION
The classic serotonergic psychedelic/hallucinogen lysergic
acid diethylamide (LSD) was widely studied in humans in
the 1950s to 1970s. However, little to no clinical research on
LSD has been conducted since then (Nichols, 2016; Passie
et al, 2008). Today, LSD is again the focus of clinical
investigations, including experimental studies in healthy
subjects (Carhart-Harris et al, 2016,2015; Dolder et al, 2015b;
Schmid et al, 2015; Strajhar et al, 2016), and clinical trials that
evaluate LSD-assisted psychotherapy (Gasser et al, 2014).
LSD that was administered only a few times decreased
anxiety and increased quality of life over a period of
12 months in patients with anxiety associated with terminal
illness (Gasser et al, 2015). The acute LSD experiences were
hypothesized to lead to a restructuring of the person's
emotional trust and situational understanding (Gasser
et al, 2015). Similar to LSD, the serotonergic hallucinogen
psilocybin and serotonin (5-hydroxytryptamine (5-HT))
releaser 3,4-methylenedioxymethamphetamine (MDMA;
ecstasy) have been used to facilitate psychotherapy in
clinical trials (Grob et al, 2011; Mithoefer et al, 2010;
Oehen et al, 2013). Psilocybin reduced anxiety at 3 months
and additionally improved mood at 6 months after treatment
in patients with advanced-stage cancer (Grob et al, 2011).
Additionally, psilocybin was recently studied as a treatment
for tobacco (Johnson et al, 2014) and alcohol (Bogenschutz
et al, 2015) dependence. MDMA-assisted psychotherapy
reduced symptoms of post-traumatic stress disorder at
2 months (Mithoefer et al, 2010), and the benefits of MDMA
were reportedly sustained for several years (Mithoefer et al,
2013). These first findings from modern clinical studies with
psychedelics and MDMA should be confirmed in larger
trials. Exploring the mechanisms that may contribute to
these beneficial and lasting effects after only a few
administrations of the substances is also important.
Studies that use psychedelics and MDMA in healthy
subjects are well suited to assess the mechanism of action of
these substances. Both LSD and psilocybin appear to produce
effects that last beyond the acute drug response in both
patients and healthy subjects. Specifically, LSD increased
optimism and trait openness at 2 weeks (Carhart-Harris et al,
2016), and psilocybin produced positive changes in attitudes,
mood, and behavior at 2 (Griffiths et al, 2006) and 14 months
(Griffiths et al, 2011) after administration. Psilocybin
increased personality trait openness in participants who
had mystical experiencesduring their psilocybin session
(MacLean et al, 2011). Therefore, some of the lasting
beneficial effects appear to be associated with an acute
psychedelic response, including a peakor mystical
experience (Carhart-Harris et al, 2016; MacLean et al, 2011).
Both LSD and psilocybin are 5-HT
2A
receptor agonists,
and their psychedelic effects are mediated by 5-HT
2A
*Correspondence: Professor ME Liechti, Department of Biomedicine
and Department of Internal Medicine, Division of Clinical Pharmacology
and Toxicology, University Hospital Basel, Hebelstrasse 2, Basel CH-4031,
Switzerland, Tel: +41 61 328 68 68, Fax: +41 61 265 45 60,
E-mail: matthias.liechti@usb.ch
Received 4 March 2016; revised 26 April 2016; accepted 18 May 2016;
accepted article preview online 1 June 2016
Neuropsychopharmacology (2016) 41, 2638 2646
Official journal of the American College of Neuropsychopharmacology
www.neuropsychopharmacology.org
receptor stimulation (Vollenweider et al, 1998). The long-
term effects of LSD and psilocybin may be related to their
psychedelic and 5-HT
2A
receptor activation properties. In
contrast to the psychedelics LSD and psilocybin, MDMA
is considered an empathogen (entactogen) that mainly
enhances positive feelings, empathy, and prosociality
(Hysek et al, 2014a; Kirkpatrick et al, 2014) while having
few hallucinogen-like effects. Additionally, MDMA has been
shown to positively alter emotion processing (Bedi et al,
2010; Hysek et al, 2012,2014a; Kirkpatrick et al, 2012,2014;
Schmid et al, 2014). These acute effects of MDMA on
emotion processing and social behavior may be beneficial
during psychotherapy in the absence of a full psychedelic
peak experience. LSD also produced acute MDMA-like
subjective effects, including greater well-being, happiness,
closeness to others, openness, and trust (Schmid et al, 2015).
Thus, LSD and MDMA may have common effects on the
processing of emotional information with relevance to their
positive acute and possibly long-term effects during
psychotherapy. However, the effects of LSD in tests of
emotion processing are unknown. Therefore, the present
study investigated the acute effects of LSD using the Face
Emotion Recognition Task (FERT) and Multifaceted Em-
pathy Test (MET). The effects of LSD on social behavior
were also evaluated using the Social Value Orientation (SVO)
test. Additionally, we assessed the subjective mood effects of
LSD using Visual Analog Scales (VASs) and the Adjective
Mood Rating Scale (AMRS), vital signs, and adverse effects.
We hypothesized that LSD would impair the recognition of
negative emotions on the FERT and enhance emotional
empathy on the MET and prosociality on the SVO test.
MATERIALS AND METHODS
Study Design
We pooled data from two similar studies using double-blind,
placebo-controlled, crossover designs with two experimental
test sessions (LSD and placebo) in a balanced order. Study 1
used a dose of 100 μg LSD and placebo in 24 subjects. Study 2
used 200 μg LSD or placebo in 16 subjects. The washout
periods between sessions were at least 7 days. The studies
were conducted in accordance with the Declaration of
Helsinki and approved by the local ethics committee. The
administration of LSD to healthy subjects was authorized by
the Swiss Federal Office for Public Health, Bern, Switzerland.
All of the subjects provided written consent before
participating in either of the studies, and they were paid
for their participation. The studies were registered at
ClinicalTrials.gov (NCT02308969, NCT01878942). The sub-
jective, endocrine, and pharmacokinetic effects of LSD in
Study 2 were previously reported (Dolder et al, 2015b;
Schmid et al, 2015; Strajhar et al, 2016).
Participants
Forty healthy participants were recruited from the University
of Basel campus via online advertisement. Twenty-four
subjects (12 men, 12 women; 33 ±11 years old (mean ±SD);
range, 2560 years) participated in Study 1, and 16 subjects
(8 men, 8 women; 29 ±6 years old; range, 2551 years)
participated in Study 2. The inclusion and exclusion criteria
were identical for both studies. Subjects younger than 25
years of age were excluded from participating in the study.
Additional exclusion criteria were age 465 years, pregnancy
(urine pregnancy test at screening and before each test
session), personal or family (first-degree relative) history of
major psychiatric disorders (assessed by the semistructured
clinical interview for Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, Axis I disorders by the study
physician and an additional interview by a trained psychia-
trist), use of medications that may interfere with the study
medication, chronic or acute physical illness (abnormal
physical exam, electrocardiogram, or hematological and
chemical blood analyses), tobacco smoking (410 cigar-
ettes/day), lifetime prevalence of illicit drug use 410 times
(except for tetrahydrocannabinol), illicit drug use within the
last 2 months, and illicit drug use during the study
(determined by urine drug tests). The subjects were asked
to abstain from excessive alcohol consumption between test
sessions and particularly limit their use to one standard drink
on the day before the test sessions. Additionally, the
participants were not allowed to drink xanthine-containing
liquids after midnight before the study day. Eleven subjects
had used a hallucinogen including LSD (6 participants) one
to three times, and most of the subjects (29) were
hallucinogen-naïve (Supplementary Table S1). We per-
formed urine drug tests at screening and before each test
session, and no substances were detected during the study.
Study Procedures
Each study included a screening visit, a psychiatric interview,
two 25-h experimental sessions, and an end-of-study visit.
The experimental sessions were conducted in a quiet
standard hospital patient room. The participants were resting
in hospital beds except when going to the restroom. Only one
research subject and one investigator were present during
the experimental sessions. Participants could interact with
the investigator, rest quietly and/or listen to music via
headphones, but no other entertainment was provided. LSD
or placebo was administered at 0900 hours. The subjects
were never alone during the first 12 h after drug adminis-
tration, and the investigator was in a room next to the subject
for up to 24 h while subjects were asleep (mostly from 0100
to 0800 hours). Because subjective responses to LSD are
pronounced and peak at 23 h and last up to 12 h (Passie
et al, 2008; Schmid et al, 2015), effects on emotion processing
and prosociality were assessed 5 and 7 h after the 100 and
200 μg doses, respectively, when the subjective effects of LSD
amounted to approximately 50% of the peak responses
(Dolder et al, 2015b; Schmid et al, 2015).
Study Drug
LSD (D-LSD hydrate; Lipomed AG, Arlesheim, Switzerland)
was administered in single oral doses of 100 or 200 μg. Both
doses are within the range of doses that are taken for
recreational purposes (Passie et al, 2008).
Measures
Facial Emotion Recognition Task. We used the FERT,
which is sensitive to the effects of other psychoactive
LSD and emotion processing
PC Dolder et al
2639
Neuropsychopharmacology
substances, including serotonin and norepinephrine uptake
inhibitors (Harmer et al, 2004), MDMA (Bedi et al, 2010;
Hysek et al, 2014b; Kirkpatrick et al, 2014; Schmid et al,
2014), and methylphenidate (Hysek et al, 2014b; Schmid
et al, 2014). The task included 10 neutral faces and 160 faces
that expressed one of four basic emotions (ie, happiness,
sadness, anger, and fear), with pictures morphed between 0%
(neutral) and 100% in 10% steps. Two female and two male
pictures were used for each of the four emotions. The stimuli
were presented in random order for 500 ms and then were
replaced by the rating screen where participants had to
indicate the correct emotion. The outcome measure was
accuracy (proportion correct). The FERT was performed 5
and 7 h after the 100 and 200 μg doses of LSD, respectively.
Multifaceted Empathy Test. The MET is a reliable and
valid task that assesses the cognitive and emotional aspects of
empathy (Dziobek et al, 2008). The MET has been shown to
be sensitive to oxytocin (Hurlemann et al, 2010), MDMA
(Hysek et al, 2014a; Kuypers et al, 2014; Schmid et al, 2014),
and psilocybin (Preller et al, 2015). The computer-assisted
test consisted of 40 photographs that showed people in
emotionally charged situations. To assess cognitive empathy,
the participants were required to infer the mental state of the
subject in each scene and indicate the correct mental state
from a list of four responses. Cognitive empathy was defined
as the percentage of correct responses relative to total
responses. To measure emotional empathy, the subjects were
asked to rate how much they were feeling for an individual in
each scene (ie, explicit emotional empathy) and how much
they were aroused by each scene (ie, implicit emotional
empathy) on a 19 point scale. The latter rating provides an
inherent additional assessment of emotional empathy, which
is considered to reduce the likelihood of socially desirable
answers. The three aspects of empathy were each tested with
20 stimuli with positive valence and 20 stimuli with negative
valence, resulting in a total of 120 trials. The MET was
performed 5 h and 30 min after the 100 μg LSD dose and 7 h
and 30 min after the 200 μg LSD, respectively.
SVO test. We used the paper version of the validated SVO
test to assess social behavior (Murphy et al, 2011). The SVO
measure was previously shown to be sensitive to MDMA
(Hysek et al, 2014a). In this economic resource allocation
task, prosociality is defined as behavior that maximizes the
sum of resources for the self and others and minimizes the
difference between the two. The test consists of six primary
and nine secondary SVO slider items with a resource
allocation choice over a defined continuum of joint payoffs
(Murphy et al, 2011). The participants were instructed to
choose a resource allocation that defined their most
preferred joint distribution between themselves and another
person. The allocated funds had real value, and four
randomly selected subjects received the funds they earned.
Mean allocations for the self and the other were calculated
(Hysek et al, 2014a; Murphy et al, 2011), and the inverse
tangent of the ratio of these two means produced an angle
that indicated the participantsSVO index. A smaller SVO
angle indicates more individualistic or competitive behavior,
and a larger SVO angle indicates more prosocial or even
altruistic behavior. The SVO was performed 6 and 8 h after
the 100 and 200 μg doses of LSD, respectively.
Subjective mood. The VASs and the AMRS (Janke and
Debus, 1978) were repeatedly used to assess subjective effects
including aspects of empathy and sociality (Hysek et al,
2014a; Schmid et al, 2015) (Supplementary Material and
Methods).
Vital signs and adverse effects. Blood pressure, heart rate,
body temperature, pupil diameter, and adverse effects were
measured as described in the Supplementary Material and
Methods.
Drug concentrations. Blood samples for the analysis of
plasma LSD levels were collected in lithium heparin tubes
after completing the social cognitive tests 6 and 8 h after
administration of the 100 and 200 μg doses of LSD or
placebo, respectively. Plasma LSD concentrations were
determined using liquid-chromatography tandem mass
spectrometry (Dolder et al, 2015a).
Statistical Analyses
All of the data were analyzed using repeated measures
analysis of variance (ANOVA), with drug (LSD vs placebo)
as the within-subjects factor and dose (100 vs 200 μg) as the
between-subjects factor, followed by the Tukeyspost hoc test
based on significant main effects or interactions. Repeated
subjective measures were expressed as peak effects prior to
the ANOVAs. Additionally, differences at individual time
points were also compared using paired t-tests. Modulatory
effects by sex or previous hallucinogen use were excluded by
adding sex or substance use as an additional factor to the
ANOVAs. Sex or previous substance use did not moderate
outcome measures.
RESULTS
Facial Emotion Recognition
The effects of LSD on the FERT are shown in Figure 1. Data
were missing from 2 of the 24 subjects in the 100 μg LSD
dose group because of technical problems. LSD impaired the
recognition of fearful faces (main effect of drug: F
1,36
=20.71,
po0.001), with no drug × dose interaction. Impairments
were found in both the 100 and 200 μg dose groups
compared with placebo (po0.01 and po0.05, respectively).
A significant main effect of drug (F
1,36
=7.36, p=0.01)
indicated that LSD also impaired the recognition of sad faces,
but post hoc comparisons of the two dose groups with
placebo did not reach significance. No significant effects of
LSD on the decoding of neutral, happy, or angry facial
expressions were found.
Empathy
The effects of LSD on explicit emotional and cognitive
empathy are shown in Figure 2. Data were missing from 2 of
the 24 subjects in the 100 μg LSD dose group because of
technical problems. There were significant main effects of
drug on explicit and implicit emotional empathy ratings
LSD and emotion processing
PC Dolder et al
2640
Neuropsychopharmacology
(F
1,36
=14.05, po0.001 and F
1,36
=6.71, p=0.01, respec-
tively), indicating that LSD increased both aspects of
emotional empathy. The post hoc tests showed that the
200 μg dose but not the 100 μg dose of LSD produced a
significant effect on explicit (po0.01) and implicit (p=0.01)
empathy scores compared with placebo. The valence-specific
analysis showed that LSD significantly increased explicit and
implicit emotional empathy scores for positive emotional
stimuli ( F
1,36
=24.32, po0.001 and F
1,36
=10.47, po0.01,
respectively) but there were only trend effects for negative
emotional stimuli (F
1,36
=3.29, p=0.08 and F
1,36
=2.82,
p=0.1, respectively). LSD decreased cognitive empathy,
reflected by a significant main effect of drug (F
1,36
=16.87,
po0.001). The post hoc tests showed that this effect was
significant for both the 100 and 200 μg doses compared with
the respective placebo conditions (both po0.05).
Social Value Orientation
A significant effect of drug was found on the SVO angle
(F
1,38
=4.31, po0.05), indicating that LSD increased proso-
ciality. The post hoc tests showed that this effect did not
reach significance in the individual LSD dose groups and was
only evident in the larger total study sample.
Subjective Mood Effects
Subjective effects on the VASs are shown in Figure 3, and
maximal values are presented in Table 1. LSD increased
maximal VAS rating scores, including those reflecting
empathy and prosociality such as feeling close to others,
open,trust, and I want to be with others, with greater
peak effects at the higher compared with the lower dose.
Ratings of happywere similarly increased by both doses.
LSD produced small dose-dependent increases in bad drug
effectand fear(Figure 3, Table 1). On the AMRS, LSD
significantly increased ratings of well-being,emotional
excitation,inactivity,introversion, and dreaminess
compared with placebo (Figure 4 and Table 1). There was
a significant main effect of LSD on fearbut no significant
effects in the individual studies.
Vital Signs and Adverse Effects
Peak values and statistics are shown in Table 1. Compared
with placebo, LSD increased blood pressure, heart rate, and
body temperature as well as pupil size in the dark and after a
light stimulus (Table 1). These effects were similar for both
doses (no drug × dose interaction). Compared with placebo,
both doses of LSD increased the total acute (010 h) adverse
effects. Only the high dose increased the total subacute
(1024 h) adverse effects. Adverse effects 2472 h were
slightly increased in the total sample but not in the individual
studies (Table 1). The frequently reported adverse effects are
presented in Supplementary Table S2. There were no severe
adverse events.
Plasma Drug Levels and Correlations Between Effects
Plasma concentrations of LSD were 0.7 ±0.3 ng/ml (mean ±SD)
6 h after administration of the 100 μgdoseand1.3±0.6 ng/ml
8 h after administration of the 200 μg dose. These time points of
blood sample collection were immediately after the social
cognitive tests performed in the respective dose groups. Plasma
Figure 1 Lysergic acid diethylamide (LSD) impaired fear recognition on
the Face Emotion Recognition Task . LSD also impaired the decoding of sad
faces (significant main effect of drug), but the effects did not reach statistical
significance in the individual dose groups. The data are expressed as
mean ±SEM in 22 and 16 subjects in the 100 and 200 μg LSD dose groups,
respectively. *po0.05, **po0.01, significant difference from placebo.
Figure 2 Lysergic acid diethylamide (LSD) increased emotional empathy
and decreased cognitive empathy on the Multifaceted Empathy Test. The
data are expressed as mean ±SEM in 22 and 16 subjects in the 100 and
200 μg LSD dose groups, respectively. *po0.05, **po0.01, significant
difference from placebo.
LSD and emotion processing
PC Dolder et al
2641
Neuropsychopharmacology
LSD levels correlated with explicit emotional empathy scores on
the MET for positive (Spearman R
s
=0.37, po0.05, n=38) but
not for negative emotional situations. Plasma levels of LSD
werenotassociatedwithFERTorSVOtestmeasures.
Plasma levels of LSD were associated with LSD-induced ratings
of trust (Spearman R
s
=0.32, po0.05, n=40). LSD-induced
VAS ratings for feelings of closenessand trustwere associated
with greater explicit empathy for positive emotional stimuli
(Spearman R
s
=0.35, po0.05 and R
s
=0.47, po0.01, respec-
tively, n=38).
DISCUSSION
LSD positively altered the processing of emotional informa-
tion by decreasing the recognition of fearful and sad faces
and enhancing emotional empathy and prosociality. We are
aware of no other published data on the acute effects of LSD
on emotion processing. However, MDMA produced very
similar effects to those of LSD in the present study. MDMA
reduced the recognition of sad and fearful faces but not
happy faces on the FERT (Bedi et al, 2010; Hysek et al,
2014b), increased explicit and implicit emotional empathy on
the MET (Hysek et al, 2014a; Kuypers et al, 2014) (mainly for
positive emotionally charged situations) (Hysek et al, 2014a;
Schmid et al, 2014), and increased prosociality on the SVO
test (Hysek et al, 2014a). LSD did not facilitate perception of
happiness in the FERT similar to MDMA (Bedi et al, 2010;
Hysek et al, 2014b), possibly because detection of positive
basic emotions is very accurate in healthy subjects and
difficult to enhance. Thus, the 5-HT
2A
receptor agonist LSD
and 5-HT releaser MDMA may produce overall similar
effects on the processing of emotional information. However,
in contrast to MDMA, LSD also impaired cognitive empathy
on the MET, and the higher dose also decreased the
recognition of neutral faces on the FERT, indicating
nonspecific performance effects. Similar to LSD, the
5-HT
2A
receptor agonist psilocybin decreased the recogni-
tion of negative facial expressions (Kometer et al, 2012) and
increased emotional empathy on the MET (Preller et al,
2015). Altogether, these findings indicate that LSD affects
emotion processing similarly to MDMA and psilocybin.
The marked acute psychedelic/hallucinogenic peak
responseto LSD and psilocybin has been considered
relevant to their lasting effects (Carhart-Harris et al, 2016;
Griffiths et al, 2011). The present study showed that LSD has
dose-dependent subjective effects on empathogenic mood,
including feelings of closeness to others,wanting to be
with others,happiness,’‘openness,and trust(Schmid
et al, 2015), in addition to more hallucinogen-specific
Figure 3 Subjective effects of lysergic acid diethylamide (LSD) over time on the Visual Analog Scales (VASs). LSD or placebo was administered at t=0. The
data are expressed as mean ±SEM in 24 and 16 subjects in the 100 and 200 μg LSD dose groups, respectively. LSD significantly increased ratings on all VASs
with significant doseresponse effects, except for ratings of happy. The corresponding maximal effects and statistics are shown in Table 1. Emotion
recognition (Face Emotion Recognition Task), empathy (Multifaceted Empathy Test), and social value orientation (SVO) tests were conducted 56 and 78h
after the administration of the 100 and 200 μg LSD dose, respectively. +/*po0.05, ++/**po0.01, +++/***po0.001 for the 100/200 μg LSD dose,
respectively, compared with placebo (T-tests).
LSD and emotion processing
PC Dolder et al
2642
Neuropsychopharmacology
psychedelic peak effects. These acute subjective effects of
LSD and its effects on the emotion processing and behavioral
tests in the present study are very similar to those of the
prototypic empathogen MDMA. However, LSD induced
higher AMRS intro- than extroversion while MDMA
produced more extro- than introversion (Hysek et al,
2014a). Importantly, the subjective feelings of happiness,
trust,closeness to others,anddesire to be with othersat
the high dose of LSD were maintained up to 612 h, and the
effects of LSD on emotion processing and prosociality were
also observed late in time at 68 h after LSD administration
and after the peak response when a plateau phasewas
reached. At that time, the subjects were also less over-
whelmed by initially strong and mostly novel psychedelic
experiences, which may open a window for psychother-
apeutic interventions. The emotional effects during the
later phase of the acute LSD response (610 h) are likely
beneficial to acutely facilitating the therapeutic alliance.
Future research should address the relative contribu-
tions of the psychedelic peak experience vs empathogenic
Table 1 Values and Statistics for the Subjective and Cardiovascular Peak Effects
Placebo 100 μg
(mean ±SE)
LSD 100 μg
(mean ±SE)
Placebo 200 μg
(mean ±SE)
LSD 200 μg
(mean ±SE)
Drug Drug × Dose
F
1,38
=p=F
1,38
=p=
Subjective effects
Visual Analog Scales (VAS, %)
Any drug effect 0.9 ±0.6 87.5 ±3.3*** 0.1 ±0.1 97.2 ±1.7***# 1939 *** 6.21 *
Good drug effect 0.9 ±0.6 85.2 ±3.4*** 0.1 ±0.1 96.8 ±1.5***## 1661 *** 7.66 **
Bad drug effect 0.0 ±0.0 17.3 ±3.6** 0.1 ±0.06 40.0 ±8.2***### 51.17 *** 8.01 **
Fear 0.0 ±0.0 8.4 ±2.3 0.06 ±0.1 31.3 ±8.6***### 27.74 *** 9.24 **
Happy 1.2 ±0.6 30 ±3.4*** 5.0 ±2.0 39.1 ±4.2*** 141.5 *** 1 NS
Closeness to others 0.0 ±0.0 15.2 ±3.2*** 4.3 ±1.8 32.3 ±4.7***### 61.68 *** 5.38 *
Open 0.2 ±0.2 17.0 ±2.8*** 3.9 ±1.5 41.0 ±3.6***### 128.9 *** 18.4 ***
Trust 0.0 ±0.0 22.0 ±4.1*** 4.8 ±2.1 39.8 ±4.0***### 81.37 *** 4.2 *
I want to be hugged 0.0 ±0.0 8.8 ±2.7 3.4 ±1.9 27.8 ±6.8***### 23.52 *** 5.13 *
I want to hug someone 0.0 ±0.0 10.4 ±2.7* 1.4 ±3.3 27.6 ±6.1***## 41.21 *** 9.13 **
I want to be alone 0.6 ±0.6 7.7 ±2.5 5.1 ±1.9 17.6 ±5.6 9.93 ** 0.76 NS
I want to be with other people 0.8 ±0.8 12.8 ±2.5** 10.8 ±4.2 42.8 ±5.5***### 79.87 *** 16.25 ***
Adjective Mood Rating Scale (AMRS, Δscore)
Well-being 0.0 ±0.6 2.5 ±1.0 1.8 ±0.7 6.6 ±1.6* 11.49 ** 1.11 NS
Emotional excitation 0.3 ±0.2 2.3 ±0.5** 0.3 ±0.3 4.7 ±1.0***## 53.5 *** 4.77 *
Inactivity 2.6 ±0.7 9.0 ±1.1** 1.3 ±1.1 10.6 ±2.7*** 30.82 *** 1.05 NS
Extroversion 0.5 ±0.3 0.1 ±0.6 0.1 ±0.5 1.5 ±0.7 2.67 NS 0.77 NS
Introversion 0.4 ±0.1 4.1 ±0.6*** 0.5 ±0.4 4.3 ±0.8*** 51.92 *** 0.01 NS
Fear 0.1 ±0.1 0.9 ±0.3 0.4 ±0.3 1.3 ±1.0 9.51 ** 0.72 NS
Dreaminess 0.2 ±0.3 6.9 ±0.7*** 0.8 ±0.5 7.9 ±0.6*** 160.2 *** 0.11 NS
Vital signs
Systolic blood pressure (mm Hg) 129 ±2.0 142 ±2.1*** 133 ±3.8 148 ±2.9*** 63.8 *** 0.13 NS
Diastolic blood pressure (mm Hg) 76.9 ±1.5 85.7 ±1.7*** 78.2±2.0 87.6 ±1.9*** 68.8 *** 0.08 NS
Heart rate (beats/min) 70.6 ±1.8 79.1 ±2.7** 72.8 ±2.6 86.9 ±4.29*** 33.7 *** 2.05 NS
Body temperature (Δ°C) 0.5 ±0.1 0.8 ±0.1** 0.3 ±0.1 0.7 ±0.1** 23.74 *** 0.22 NS
Pupil size (mm) 6.1 ±0.2 6.9 ±0.1*** 6.5 ±0.2 7.2 ±0.1*** 61.08 *** 0.81 NS
Pupil size after light (mm) 4.3 ±0.2 5.2 ±0.2*** 4.6 ±0.2 5.6 ±0.2*** 89.61 *** 0.02 NS
List of complaints (ΔLC total score)
Acute adverse effects (010 h) 0.5 ±0.3 9.8 ±1.8*** 0.1 ±0.6 10.4 ±3.0*** 38.37 *** 0 NS
Subacute adverse effects (1024 h) 0.2 ±0.3 0.4 ±0.2 0.4 ±0.4 3.7 ±1.4** 12.06 ** 6.76 *
Subacute adverse effects (2472 h) 0.5 ±0.3 0.1 ±0.2 0.8 ±0.4 0.6 ±0.9 6.03 * 1.83 NS
Values are mean ±SEM of the peak or peak changes (Δ) from baseline in 40 subjects. Sixteen subjects participated in the high dose study (200 μg) and 24 subjects in the
moderate dose study (100 μg).
*for po0.05, **for po0.01, ***for po0.001 compared with placebo. # for po0.05, ## for po0.01, ### for po0.001 compared with LSD 100 μg.
LSD and emotion processing
PC Dolder et al
2643
Neuropsychopharmacology
emotional effects of LSD to its potential therapeutic effects.
Additionally, it seems that only the higher 200 μg dose of
LSD produced robust empathogenic effects. Furthermore,
the relevance of deficits in cognitive empathy for the
therapeutic process is unclear.
The present study also showed that LSD was well tolerated
in a controlled setting in healthy subjects. Adverse effects of
LSD mainly included acute dizziness, headache, and fatigue/
exhaustion lasting up to 72 h. Both doses of LSD produced
comparable moderate sympathomimetic effects including
elevated blood pressure, heart rate, body temperature, and
mydriasis.
The present study used two doses of LSD within a
clinically relevant dose range. In fact, the higher dose was
identical to both the amount and pharmaceutical formula-
tion that were used in a clinical study in patients with anxiety
(Gasser et al, 2014) and continue to be used in patients in
Switzerland. Additionally, LSD was administered to subjects
across a relatively wide age range (2560 years). Importantly,
the subjects typically had no or very limited hallucinogen
experience, which is possibly similar to cases in which LSD is
used therapeutically in patients. In contrast, other contem-
porary studies used lower doses of LSD in subjects with
extensive prior substance use (Carhart-Harris et al,
2016,2015). However, in the present study, previous
hallucinogen use (13 times including LSD in six subjects)
did not alter the responses to LSD.
In the present study, the tests were performed approxi-
mately 3 h after the peak effects (Dolder et al, 2015b; Schmid
et al, 2015). At the time of the peak response of LSD, test
administration would not have been feasible because of the
strong alterations in wake consciousness and impairments in
concentration (Schmid et al, 2015). The participants needed
to adjust to the altered state of consciousness; therefore,
testing occurred after a plateau phasewas reached. Never-
theless, at the time of testing, the subjective effects and plasma
concentrations of LSD were still at approximately 50% of the
peak responses and clearly effective in producing typical LSD
effects, providing a good time interval for conducting the
neurocognitive tasks (Carhart-Harris et al, 2016; Schmid et al,
2015). Additionally, the tests were performed later after the
high dose than after the low dose of LSD. However, at the
times of testing, plasma LSD concentrations were twice as
high after the 200 μg dose compared with the 100 μg dose, and
generating a dose/concentrationresponse effect was possible.
The study has limitations. First, the dose effects of LSD
were studied in different participants and not within-subject.
Second, we assessed only emotion recognition and no other
measures such as face muscle responses to emotions (Wardle
et al, 2014) and the stimuli were artificial (pictures) rather
than real people. With regard to the use of LSD in
psychotherapy, we only assessed empathic concern for
othersbut not whether the participants felt cared for or
understood by someone else(Wardle and de Wit, 2014). It is
possible that LSD affected attention and motivation and
thereby task performance. Thus, it will be important to
replicate and expand our findings using additional emotion
recognition tests (Wardle and de Wit, 2014), tests of
responses to emotions (Wardle and de Wit, 2014; Wardle
et al, 2014), and other measures of social interaction (Frye
et al, 2014).
Figure 4 Subjective effects on the Adjective Mood Rating Scale. Lysergic acid diethylamide (LSD) or placebo was administered at t=0. The data are
expressed as mean ±SEM changes from baseline (1 h) in 24 and 16 subjects in the 100 and 200 μg LSD dose groups, respectively. Emotion recognition
(Face Emotion Recognition Task), empathy (Multifaceted Empathy Test), and social value orientation (SVO) tests were conducted 56 and 78 h after the
administration of the 100 and 200 μg LSD dose, respectively. The corresponding maximal effects and statistics are shown in Table 1. *po0.05, **po0.01,
***po0.001 compared with placebo (T-tests).
LSD and emotion processing
PC Dolder et al
2644
Neuropsychopharmacology
In conclusion, LSD impaired emotion recognition of
negative emotions and enhanced emotional empathy,
particularly for positive emotional situations, and had
subjective and behaviorally tested prosocial effects. These
effects of LSD in healthy participants likely have translational
relevance to LSD-assisted psychotherapy in patients and can
be expected to reduce the perception of negative emotions
and facilitate the therapeutic alliance.
FUNDING AND DISCLOSURE
This work was supported by the Swiss National Science
Foundation (grant no. 320030_1449493 to MEL) and the
University of Basel (to FM). The authors declare no conflict
of interest.
ACKNOWLEDGMENTS
We acknowledge the assistance of M Arends in text
editing. The studies were registered at ClinicalTrials.gov
(NCT02308969, NCT01878942).
REFERENCES
Bedi G, Hyman D, de Wit H (2010). Is ecstasy an empathogen?
Effects of ±3,4-methylenedioxymethamphetamine on prosocial
feelings and identification of emotional states in others. Biol
Psychiatry 68: 11341140.
Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE,
Barbosa PC, Strassman RJ (2015). Psilocybin-assisted treatment
for alcohol dependence: a proof-of-concept study. J Psychophar-
macol 29: 289299.
Carhart-Harris RL, Kaelen M, Bolstridge M, Williams TM,
Williams LT, Underwood R et al (2016). The paradoxical
psychological effects of lysergic acid diethylamide (LSD). Psychol
Med 46: 13791390.
Carhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M,
Feilding A, Nutt DJ (2015). LSD enhances suggestibility in
healthy volunteers. Psychopharmacology 232: 785794.
Dolder PC, Liechti ME, Rentsch KM (2015a). Development and
validation of a rapid turboflow LC-MS/MS method for the
quantification of LSD and 2-oxo-3-hydroxy LSD in serum and
urine samples of emergency toxicological cases. Anal Bioanal
Chem 407: 15771584.
Dolder PC, Schmid Y, Haschke M, Rentsch KM, Liechti ME (2015b).
Pharmacokinetics and concentration-effect relationship of oral LSD
in humans. Int J Neuropsychopharmacol (doi:10.1093/ijnp/pyv072).
Dziobek I, Rogers K, Fleck S, Bahnemann M, Heekeren HR, Wolf OT
et al (2008). Dissociation of cognitive and emotional empathy in
adults with Asperger syndrome using the Multifaceted Empathy
Test (MET). JAutismDevDisord38:464473.
Frye CG, Wardle MC, Norman GJ, de Wit H (2014). MDMA
decreases the effects of simulated social rejection. Pharmacol
Biochem Behav 117:16.
Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B,
Passie T et al (2014). Safety and efficacy of lysergic acid
diethylamide-assisted psychotherapy for anxiety associated with
life-threatening diseases. J Nerv Ment Dis 202: 513520.
Gasser P, Kirchner K, Passie T (2015). LSD-assisted psychotherapy
for anxiety associated with a life-threatening disease: a qualitative
study of acute and sustained subjective effects. J Psychopharmacol
29:5768.
Griffiths RR, Johnson MW, Richards WA, Richards BD,
McCann U, Jesse R (2011). Psilocybin occasioned mystical-type
experiences: immediate and persisting dose-related effects.
Psychopharmacology 218: 649665.
Griffiths RR, Richards WA, McCann U, Jesse R (2006). Psilocybin
can occasion mystical-type experiences having substantial and
sustained personal meaning and spiritual significance. Psycho-
pharmacology 187: 268283 discussion 284-292.
Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR,
Halberstadt AL et al (2011). Pilot study of psilocybin treatment
for anxiety in patients with advanced-stage cancer. Arch Gen
Psychiatry 68:7178.
Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM (2004). Increased
positive versus negative affective perception and memory in
healthy volunteers following selective serotonin and norepinephr-
ine reuptake inhibition. Am J Psychiatry 161: 12561263.
Hurlemann R, Patin A, Onur OA, Cohen MX, Baumgartner T,
Metzler S et al (2010). Oxytocin enhances amygdala-dependent,
socially reinforced learning and emotional empathy in humans.
J Neurosci 30: 49995007.
Hysek CM, Domes G, Liechti ME (2012). MDMA enhances mind
readingof positive emotions and impairs mind readingof
negative emotions. Psychopharmacology 222: 293302.
Hysek CM, Schmid Y, Simmler LD, Domes G, Heinrichs M,
Eisenegger C et al (2014a). MDMA enhances emotional empathy
and prosocial behavior. Soc Cogn Affect Neurosci 9: 16451652.
Hysek CM, Simmler LD, Schillinger N, Meyer N, Schmid Y,
Donzelli M et al (2014b). Pharmacokinetic and pharmacody-
namic effects of methylphenidate and MDMA administered alone
and in combination. Int J Neuropsychopharmacol 17: 371381.
Janke W, Debus G (1978). Die Eigenschaftswörterliste. Hogrefe:
Göttingen.
Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR (2014).
Pilot study of the 5-HT
2A
R agonist psilocybin in the treatment of
tobacco addiction. J Psychopharmacol 28: 983992.
Kirkpatrick MG, Gunderson EW, Perez AY, Haney M, Foltin RW,
Hart CL (2012). A direct comparison of the behavioral and
physiological effects of methamphetamine and 3,4-methylene-
dioxymethamphetamine (MDMA) in humans. Psychopharmacol-
ogy 219: 109122.
Kirkpatrick MG, Lee R, Wardle MC, Jacob S, de Wit H (2014).
Effects of MDMA and intranasal oxytocin on social and
emotional processing. Neuropsychopharmacology 39: 16541663.
Kometer M, Schmidt A, Bachmann R, Studerus E, Seifritz E,
Vollenweider FX (2012). Psilocybin biases facial recognition,
goal-directed behavior, and mood state toward positive relative to
negative emotions through different serotonergic subreceptors.
Biol Psychiatry 72: 898906.
Kuypers KP, de la Torre R, Farre M, Yubero-Lahoz S, Dziobek I,
Van den Bos W et al (2014). No evidence that MDMA-induced
enhancement of emotional empathy is related to peripheral
oxytocin levels or 5-HT1a receptor activation. PLoS One 9:
e100719.
MacLean KA, Johnson MW, Griffiths RR (2011). Mystical
experiences occasioned by the hallucinogen psilocybin lead to
increases in the personality domain of openness. J Psychophar-
macol 25: 14531461.
Mithoefer MC, Wagner MT, Mithoefer AT, Jerome I, Doblin R
(2010). The safety and efficacy of ±3,4-methylenedioxymetham-
phetamine-assisted psychotherapy in subjects with chronic,
treatment-resistant posttraumatic stress disorder: the first rando-
mized controlled pilot study. J Psychopharmacol 25: 439452.
Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF,
Yazar-Klosinski B et al (2013). Durability of improvement in
post-traumatic stress disorder symptoms and absence of harmful
effects or drug dependency after 3,4-methylenedioxymethamphe-
tamine-assisted psychotherapy: a prospective long-term follow-
up study. J Psychopharmacol 27:2839.
Murphy RO, Ackermann KA, Handgraaf MJJ (2011). Measuring
social value orientation. Judgm Decis Mak 6: 771781.
LSD and emotion processing
PC Dolder et al
2645
Neuropsychopharmacology
Nichols DE (2016). Psychedelics. Pharmacol Rev 68: 264355.
Oehen P, Traber R, Widmer V, Schnyder U (2013). A randomized,
controlled pilot study of MDMA (±3,4-methylenedioxymetham-
phetamine)-assisted psychotherapy for treatment of resistant,
chronic post-traumatic stress disorder (PTSD). J Psychopharma-
col 27:4052.
Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A
(2008). The pharmacology of lysergic acid diethylamide: a review.
CNS Neurosci Ther 14: 295314.
Preller KH, Pokorny T, Krähenmann R, Dziobek I, Stämpfli P,
Vollenweider FX (2015). The effect of 5-HT2A/1a agonist
treatment on social cognition, empathy, and social decision-
making. Eur Psychiatry 30(Suppl. 1): 22.
Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH,
Vollenweider FX et al (2015). Acute effects of lysergic acid
diethylamide in healthy subjects. Biol Psychiatry 78(8): 544553.
Schmid Y, Hysek CM, Simmler LD, Crockett MJ, Quednow BB,
Liechti ME (2014). Differential effects of MDMA and
methylphenidate on social cognition. J Psychopharmacol 28:
847856.
Strajhar P, Schmid Y, Liakoni E, Dolder PC, Rentsch KM,
Kratschmar DV et al (2016). Acute effects of LSD on
circulating steroid levels in healthy subjects. J Neuroendocrinol
(doi:10.1111/jne.12374).
Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A,
Vogel H, Hell D (1998). Psilocybin induces schizophrenia-like
psychosis in humans via a serotonin-2 agonist action. Neuroreport
9: 38973902.
Wardle MC, de Wit H (2014). MDMA alters emotional processing
and facilitates positive social interaction. Psychopharmacology
231: 42194229.
Wardle MC, Kirkpatrick MG, de Wit H (2014). 'Ecstasy' as a social
drug: MDMA preferentially affects responses to emotional stimuli
with social content. Soc Cogn Affect Neurosci 9: 10761081.
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivs 4.0
International License. The images or other third party
material in this article are included in the articles Creative
Commons license, unless indicated otherwise in the credit line;
if the material is not included under the Creative Commons
license, users will need to obtain permission from the license
holder to reproduce the material. To view a copy of this license,
visit http://creativecommons.org/licenses/by-nc-nd/4.0/
© The Author(s) 2016
Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)
LSD and emotion processing
PC Dolder et al
2646
Neuropsychopharmacology
... Unter anderem werden Personen mit einer Psychose in der Vorgeschichte oder bei Verwandten 1. Grades ausgeschlossen. Insgesamt berichtet keine der modernen Studien mit mehreren Hundert gesunden Teilnehmern und Patienten über ernsthafte Nebenwirkungen, einschliesslich HPPD und psychotischer Reaktionen (32,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). Diese Ergebnisse zeigen, dass sich Halluzinogene im klinischen Rahmen sicher anwenden lassen. ...
Article
Full-text available
Die Alkoholabhängigkeit ist eine häufige psychische Erkrankung mit erheblichen Auswirkungen auf die Betroffenen und deren Umfeld. Die aktuellen Behandlungsansätze sind wirksam, allerdings spricht ein erheblicher Teil der Patienten nur sehr unzureichend auf etablierte Therapien an. In den 1950er- und 1960er-Jahren wurden Halluzinogene, insbesondere LSD (Lysergsäurediethylamid), in der Behandlung von Patienten mit Alkoholabhängigkeit in zahlreichen Studien untersucht. Jedoch blieb bis zum Ende dieses Forschungszweigs in den 1960er-Jahren die Effektivität dieses Ansatzes aufgrund von methodischen Aspekten umstritten. Zurzeit werden mit dem verwandten Wirkstoff Psilocybin mehrere Studien durchgeführt, die viele methodische Mängel der ersten Studien nicht aufweisen. Innerhalb der nächsten Jahre sollten diese Projekte wissenschaftlich fundiertere Informationen über das Potenzial von Halluzinogenen in der Behandlung der Alkoholabhängigkeit erbringen.
... Furthermore, research has not yet examined whether the strength of the therapeutic relationship leads to treatment outcomes through its influence on acute psychedelic experiences. Additionally, despite evidence for the dynamic nature of the therapeutic relationship and suggestions that psychedelic experiences and psychedelics themselves may intensify and potentially enhance the therapeutic relationship (e.g., Grinspoon and Bakalar, 1986;Grinspoon and Doblin, 2001;Walsh and Grob, 2005;Grof, 2008;Fisher 2015;Dolder et al., 2016), research has not yet examined whether psychedelic experiences are associated with subsequent improvements in the therapeutic relationship. ...
Article
Full-text available
Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes. Methods: This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder ( N = 59). This analysis focused on the psilocybin condition ( n = 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called “Accept-Connect-Embody” (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path analyses tested the hypothesis that therapeutic alliance (Scale To Assess the Therapeutic Relationship Patient Version, STAR-P) would predict depression outcomes via its influence on the acute psychedelic experience, specifically emotional-breakthrough (EBI) and mystical-type experiences (MEQ). The same analysis was performed on the escitalopram arm to test specificity. Results: The strength of therapeutic alliance predicted pre-session rapport, greater emotional-breakthrough and mystical-type experience (maximum EBI and MEQ scores across the two psilocybin sessions) and final QIDS scores ( β = −0.22, R ² = 0.42 for EBI Max ; β = −0.19, R ² = 0.32 for MEQ Max ). Exploratory path models revealed that final depression outcomes were more strongly affected by emotional breakthrough during the first, and mystical experience during the second session. Emotional breakthrough, but not mystical experience, during the first session had a positive effect on therapeutic alliance ahead of the second session ( β = 0.79, p < 0.0001). Therapeutic alliance ahead of the second session had a direct impact on final depression scores, not mediated by the acute experience, with a weaker alliance ahead of the second psilocybin session predicting higher absolute depression scores at endpoint ( β = −0.49, p < 0.001) Discussion: Future research could consider therapist training and characteristics; specific participant factors, e.g., attachment style or interpersonal trauma, which may underlie the quality of the therapeutic relationship, the psychedelic experience and clinical outcomes; and consider how therapeutic approaches might adapt in cases of weaker therapeutic alliance. Clinical Trial Registration: This trial is registered at http://clinicaltrials.gov , identifier (NCT03429075).
Article
Psychedelic-assisted psychotherapy holds great promise in the treatment of mental health disorders. Research into 5-hydroxytryptamine 2A receptor (5-HT2AR) agonist psychedelic compounds has increased dramatically over the past two decades. In humans, these compounds produce drastic effects on consciousness, and their therapeutic potential relates to changes in the processing of emotional, social, and self-referential information. The use of animal behavior to study psychedelics is under debate, and this review provides a critical perspective on the translational value of animal behavior studies in psychedelic research. Acute activation of 5-HT2ARs produces head twitches and unique discriminative cues, disrupts sensorimotor gating, and stimulates motor activity while inhibiting exploration in rodents. The acute treatment with psychedelics shows discrepant results in conventional rodent tests of depression-like behaviors but generally induces anxiolytic-like effects and inhibits repetitive behavior in rodents. Psychedelics impair waiting impulsivity but show discrepant effects in other tests of cognitive function. Tests of social interaction also show conflicting results. Effects on measures of time perception depend on the experimental schedule. Lasting or delayed effects of psychedelics in rodent tests related to different behavioral domains appear to be rather sensitive to changes in experimental protocols. Studying the effects of psychedelics on animal behaviors of relevance to effects on psychiatric symptoms in humans, assessing lasting effects, publishing negative findings, and relating behaviors in rodents and humans to other more translatable readouts, such as neuroplastic changes, will improve the translational value of animal behavioral studies in psychedelic research. SIGNIFICANCE STATEMENT: Psychedelics like LSD and psilocybin have received immense interest as potential new treatments of psychiatric disorders. Psychedelics change high-order consciousness in humans, and there is debate about the use of animal behavior studies to investigate these compounds. This review provides an overview of the behavioral effects of 5-HT2AR agonist psychedelics in laboratory animals and discusses the translatability of the effects in animals to effects in humans. Possible ways to improve the utility of animal behavior in psychedelic research are discussed.
Article
Full-text available
The extremes of human experiences, such as those occasioned by classic psychedelics and psychosis, provide a rich contrast for understanding how components of these experiences impact well-being. In recent years, research has suggested that classic psychedelics display the potential to promote positive enduring psychologic and behavioral changes in clinical and nonclinical populations. Paradoxically, classic psychedelics have been described as psychotomimetics. This review offers a putative solution to this paradox by providing a theory of how classic psychedelics often facilitate persistent increases in well-being, whereas psychosis leads down a "darker" path. This will be done by providing an overview of the overlap between the states (i.e., entropic processing) and their core differences (i.e., self-focus). In brief, entropic processing can be defined as an enhanced overall attentional scope and decreased predictability in processing stimuli facilitating a hyperassociative style of thinking. However, the outcomes of entropic states vary depending on level of self-focus, or the degree to which the associations and information being processed are evaluated in a self-referential manner. We also describe potential points of overlap with less extreme experiences, such as creative thinking and positive emotion-induction. Self-entropic broadening theory offers a heuristically valuable perspective on classic psychedelics and their lasting effects and relation to other states by creating a novel synthesis of contemporary theories in psychology. SIGNIFICANCE STATEMENT: Self-entropic broadening theory provides a novel theory examining the psychedelic-psychotomimetic paradox, or how classic psychedelics can be therapeutic, yet mimic symptoms of psychosis. It also posits a framework for understanding the transdiagnostic applicability of classic psychedelics. We hope this model invigorates the field to provide more rigorous comparisons between classic psychedelic-induced states and psychosis and further examinations of how classic psychedelics facilitate long-term change. As a more psychedelic future of psychiatry appears imminent, a model that addresses these long-standing questions is crucial.
Article
Full-text available
This paper provides a critical review of several possible mechanisms at different levels of analysis underlying the effects and therapeutic potential of psychedelics. At the (1) biochemical level, psychedelics primarily affect the 5-HT2a receptor, increase neuroplasticity, offer a critical period for social reward learning and have anti-inflammatory properties. At the (2) neural level, psychedelics have been associated with reduced efficacy of thalamo-cortical filtering, the loosening of top-down predictive signaling and an increased sensitivity to bottom-up prediction errors, and activation of the claustro-cortical-circuit. At the (3) psychological level, psychedelics have been shown to induce altered and affective states, they affect cognition, induce belief change, exert social effects and can result in lasting changes in behavior. We outline the potential for a unifying account of the mechanisms underlying psychedelics and contrast this with a model of pluralistic causation. Ultimately, a better understanding of the specific mechanisms underlying the effects of psychedelics could allow for a more targeted therapeutic approach. We highlight current challenges for psychedelic research and provide a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.
Article
Existing pharmacological treatments for psychiatric disorders have demonstrated limited efficacy, delayed onset of action, and significant burden of side effects. Recent findings from human studies with psychedelics have shown promise, demonstrating rapid and sustained clinical benefits of these compounds for a variety of psychiatric disorders. Classical psychedelics have a rich history and some of these compounds have been used in shamanic and spiritual ceremonies for millennia. The psychoactive effects of these drugs, particularly on human consciousness, have generated great scientific curiosity, and early research on psychedelics suggested their clinical benefits for psychiatric conditions, including alcohol use disorders and anxiety and depressive symptoms in terminal illness and life-threatening conditions. Since the 1990s, after a period of dormancy that followed the criminalization of psychedelic drugs since the Controlled Substance Act of 1970, the continued interest in their unique psychoactive effects along with the pursuit for novel and more effective treatments in psychiatry have led to a renewed interest in research on these compounds. While preliminary findings on psychedelics are encouraging, current evidence is still insufficient to support extensive use of these drugs routinely. Long-term safety and efficacy of these compounds remain unclear, and several clinical trials are underway and may add clarity to these questions. Therefore, this article intends to provide an overview of the evidence to date on psychedelic drugs – particularly psilocybin, MDMA, and LSD – for the treatment of psychiatric disorders.
Article
Full-text available
This is a narrative review about the role of classic and two atypical psychedelics in the treatment of unipolar and bipolar depression. Since the 1990s, psychedelics experience a renaissance in biomedical research. The so-called classic psychedelics include lysergic acid diethylamide (LSD), psilocybin, mescaline and ayahuasca. Characteristic effects like alterations in sensory perception, as well as emotion- and self-processing are induced by stimulation of serotonin 2A receptors in cortical areas. The new paradigm of psychedelic-assisted psychotherapy suggests a therapeutic framework in which a safely conducted psychedelic experience is integrated into a continuous psychotherapeutic process. First randomized, controlled trials with psilocybin show promising efficacy, tolerability, and adherence in the treatment of unipolar depression. On the other hand, classic psychedelics seem to be associated with the induction of mania, which is an important issue to consider for the design of research and clinical protocols. So called atypical psychedelics are a heterogeneous group with overlapping subjective effects but different neurobiological mechanisms. Two examples of therapeutic value in psychiatry are 3,4-methyl enedioxy methamphetamine (MDMA) and ketamine. Since 2020 the ketamine enantiomer esketamine has been granted international approval for treatment-resistant unipolar depression, and also first evidence exists for the therapeutic efficacy of ketamine in bipolar depression. Whether psychedelics will fulfil current expectations and find their way into broader clinical use will depend on future rigorous clinical trials with larger sample sizes. A well-considered therapeutic and legal framework will be crucial for these substances to create new treatment settings and a potential paradigm shift.
Chapter
Posttraumatic stress disorder (PTSD) is a debilitating, chronic disorder and efficacy rates of current PTSD treatments are underwhelming. There is a critical need for innovative approaches. We provide an overview of trauma and PTSD and cite literature providing converging evidence of the therapeutic potential of psilocybin for PTSD. No study to date has investigated psilocybin or psilocybin-assisted psychotherapy (PAP) as treatments for PTSD. An open-label study in traumatized AIDS survivors found that PAP reduced PTSD symptoms, attachment anxiety, and demoralization. Several PAP trials show preliminary efficacy in facilitating confronting traumatic memories, decreasing emotional avoidance, depression, anxiety, pessimism, and disconnection from others, and increasing acceptance, self-compassion, and forgiveness of abusers, all of which are relevant to PTSD recovery. There is also early evidence that other classic psychedelics may produce large reductions in PTSD symptoms in combat veterans. However, this body of literature is small, mechanisms are not yet well understood, and the risks of using psychedelic compounds for trauma-related disorders need further study. In sum, evidence supports further investigation of PAP as a radically new approach for treating PTSD.
Article
Background: Psychedelics are able to acutely alter emotional reactivity and self-consciousness. However, whether the regular naturalistic use of psychedelics can be linked to more persistent trait-level changes in these domains remains an open question. Aim: To test the hypotheses that (1) using psychedelics is related to higher positive and lower negative emotional reactivity; and (2) an adaptive pattern of self-consciousness, including diminished public self-consciousness and rumination, and increased reflection and self-awareness; and (3) these relations are mediated by the intensity of past ego-dissolution and mystical experiences. Method: An online survey including questions about the history of psychoactive substance use; questionnaires measuring trait levels of emotional reactivity and self-consciousness; questionnaires for retrospective assessment of ego-dissolution and mystical experiences. Data collected from 2516 participants (1661 psychedelics users) were analyzed using robust linear regression and mediation analysis. Results: A higher number of lifetime uses of psychedelics predicted greater positive and lower negative emotional reactivity; also, in the domain of self-consciousness, it predicted greater reflection and internal state awareness, and reduced rumination tendency and public self-consciousness. Finally, the intensity of past mystical and ego-dissolution experiences mediated almost all the observed relationships between the lifetime number of psychedelics uses and psychological variables. Conclusions: Lifetime psychedelics use predicts an adaptive pattern of trait-level emotional reactivity and self-consciousness. Ego-dissolution and mystical experiences are essential in understanding the long-lasting psychological effects of psychedelics use. Our findings might potentially explain previous observations of increased well-being in psychedelics users.
Article
Psychedelic-assisted psychotherapy gained considerable interest as a novel treatment strategy for fear-related mental disorders but the underlying mechanism remains poorly understood. The serotonin 2A (5-HT2A) receptor is a key target underlying the effects of psychedelics on emotional arousal but its role in fear processing remains controversial. Using the psychedelic 5-HT2A/5-HT2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-HT2A receptor knockout (KO) mice we investigated the effect of 5-HT2A receptor activation on emotional processing. We show that DOI administration did not impair performance in a spontaneous alternation task but reduced anxiety-like avoidance behavior in the elevated plus maze and elevated zero maze tasks. Moreover, we found that DOI did not block memory recall but diminished fear expression in a passive avoidance task. Likewise, DOI administration reduced fear expression in an auditory fear conditioning paradigm, while it did not affect retention of fear extinction when administered prior to extinction learning. The effect of DOI on fear expression was abolished in 5-HT2A receptor KO mice. Administration of DOI induced a significant increase of c-Fos expression in specific amygdalar nuclei. Moreover, local infusion of the 5-HT2A receptor antagonist M100907 into the amygdala reversed the effect of systemic administration of DOI on fear expression while local administration of DOI into the amygdala was sufficient to suppress fear expression. Our data demonstrate that activation of 5-HT2A receptors in the amygdala suppresses fear expression but provide no evidence for an effect on retention of fear extinction.
Article
Full-text available
Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, but the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, but its influence on plasma steroid levels over time have not yet been characterized in humans. The effects of LSD (200μg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomized, double-blind, placebo-controlled cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone compared with placebo. The mean maximum concentration of LSD was reached at 1.7h. Mean peak psychedelic effects were reached at 2.4h, with significant alterations in mental state from 0.5h to >10h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5h and 1.9h, and significant elevations were observed 1.5-6h and 1-3h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens, or mineralocorticoids compared with placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance. This article is protected by copyright. All rights reserved.
Article
Full-text available
Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Article
Full-text available
The pharmacokinetics of oral lysergic acid diethylamide (LSD) are unknown, despite its common recreational use and renewed interest in its use in psychiatric research and practice. We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of LSD and its main metabolite after administration of a single oral dose of LSD (200 μg) in eight male and eight female healthy subjects. Plasma LSD concentrations were quantifiable (> 0.1 ng/ml) in all of the subjects up to 12 h after administration. Maximal concentrations of LSD (mean ± SD: 4.5 ± 1.4 ng/ml) were reached (median, range) 1.57 (0.5-4) h after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6 ± 0.9 h up to 12 h and slower elimination thereafter with a terminal half-life of 8.9 ± 5.9 h. One percent of the orally administered LSD was eliminated in urine as LSD, and 14% was eliminated as 2-oxo-3-hydroxy-LSD within 24 h. No sex differences were observed in the pharmacokinetic profiles of LSD. The acute subjective and sympathomimetic responses to LSD lasted up to 12 h and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. These first data on the pharmacokinetics and concentration-effect relationship of oral LSD are relevant for further clinical studies and serve as a reference for the assessment of intoxication with LSD. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Article
Full-text available
Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.
Article
Full-text available
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. 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. 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. In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-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. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Article
Full-text available
Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time-consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84 %, in urine samples and 97.40 and 5.89 % in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99 % in urine and 107 and 4.70 % in serum. Mean interday accuracy and precision for LSD were 100 and 8.26 % in urine and 101 and 6.56 % in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11 % in urine and 99.8 and 8.35 % in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80-14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml.
Article
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.
Article
Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. In particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. The 5HT-1A/2A receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. However, it is not known if this extends to negative social interaction and whether 5HT-1A/2A receptor stimulation induces changes in empathy. Given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition. In a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fMRI. Furthermore, we assessed cognitive and emotional empathy using the Multifaceted Empathy Test. The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy. These results show that the 5HT-1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. In particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.