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Archival Report
Acute Effects of Lysergic Acid Diethylamide in
Healthy Subjects
Yasmin Schmid, Florian Enzler, Peter Gasser, Eric Grouzmann, Katrin H. Preller,
Franz X. Vollenweider, Rudolf Brenneisen, Felix Müller, Stefan Borgwardt, and Matthias E. Liechti
ABSTRACT
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Keywords: Adverse effects, Hormones, LSD, Prepulse inhibition, Subjective effects, Sympathomimetic effects
http://dx.doi.org/10.1016/j.biopsych.2014.11.015
Lysergic acid diethylamide (LSD) is a prototypical classic
hallucinogen (1,2). The psychotropic effects of LSD were
discovered in 1943 by Hofmann in Basel (3). In the 1950s–
1970s, LSD was initially used as an experimental tool (“psy-
chotomimetic”) to study psychotic-like states and model
psychosis (4,5) and as an adjunct in “psycholytic psychother-
apy.”It has also been investigated for the treatment of
alcoholism (6), addiction (7), cluster headache (8), and anxiety
associated with terminal illness (9–11). Today, LSD is used
illicitly for recreational (personal or spiritual) purposes. The
lifetime prevalence of LSD use among adults is 6%–8%
(12,13). Despite the widespread recreational use, no exper-
imental scientific pharmacologic studies have been conducted
with LSD in the last 40 years, until recently (14). After the initial
psychiatric investigation by Stoll (15), several case reports and
studies in the 1950s and 1960s described aspects of the
psychological effects of LSD (5,16–18). However, these stud-
ies were not performed according to current research stand-
ards and did not include control conditions or the systematic
characterization of psychotropic effects. Many studies also
sought to describe the psychotomimetic effects of LSD but
were not designed to measure any positive subjective effects.
Modern experimental studies with hallucinogens in humans
resumed in the 1990s with N-N-dimethyltryptamine (DMT; also
known ayahuasca) (19–22), ketamine (22–24), and psilocybin
(25,26), but not with LSD. More recently, LSD and psilocybin
have been evaluated in pilot therapeutic studies as treatments
for anxiety in patients with life-threatening diseases (11,27).
Because of the continued popularity of LSD as a recreational
drug and renewed interest in its therapeutic use (11,28), we re-
examined the acute response to LSD in healthy subjects. To
allow for a better characterization of the subjective effects of
LSD, we used psychometric instruments that have been used
with other psychotropic drugs, including hallucinogens,
empathogens, and stimulants (21,22,29–32).
Serotoninergic hallucinogens, including psilocybin, DMT,
and LSD, elicit mostly visual perceptual disturbances that
resemble perceptual disturbances observed in early schizo-
phrenia (22,33–35). Hallucinogens also induce alterations in
information processing that are similar to those observed in
&2014 Society of Biological Psychiatry 1
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SEE COMMENTARY ON PAGE
schizophrenia. Specifically, prepulse inhibition (PPI) of the
acoustic startle response serves as an operational measure
of sensorimotor gating that can be assessed in animals and
humans (36). In schizophrenia, PPI is impaired in prodromal
states and early phases (36–39), and hallucinogens such as
LSD acutely disrupt PPI in animals (40–45). In animals, PPI
serves as a preclinical model of schizophrenia (46). The effects
of LSD on sensorimotor gating function have not yet been
explored in humans and were tested in the present study. We
hypothesized that LSD would produce alterations in waking
consciousness and impair PPI. Additionally, no data are
available on the acute autonomic and adverse effects of
LSD, and the endocrine effects of LSD in humans are
unknown. Up-to-date clinical safety data are mostly missing.
Because of the continued popularity of LSD as a recreational
drug and interest in its therapeutic use, we also examined the
acute somatic and endocrine response to LSD.
METHODS AND MATERIALS
Participants
We recruited 16 healthy subjects (8 men, 8 women; mean age
6SD, 28.6 66.2 years; range, 25–51 years) by word of mouth
or an advertisement placed on the web market platform of the
University of Basel. All subjects provided written informed
consent and were paid for their participation. Additionally, we
considered the safety recommendations for high-dose halluci-
nogen research (47,48). The participant characteristics are
described in detail in Supplement 1. Seven subjects had used
a hallucinogen one to three times, and another four subjects
had prior experience with methylenedioxymethamphetamine
(MDMA) (two to four times).
Study Design
A double-blind, placebo-controlled, crossover design was
used with two experimental test sessions in balanced order.
The washout periods between sessions were at least 7 days.
The study was conducted in accordance with the Declaration
of Helsinki and International Conference on Harmonization
Guidelines in Good Clinical Practice and approved by the
Ethics Committee of the Canton of Basel, Switzerland, and
Swiss Agency for Therapeutic Products (Swissmedic). The
administration of LSD to healthy subjects was authorized by
the Swiss Federal Office for Public Health, Bern, Switzerland.
The study was registered at ClinicalTrials.gov (NCT01878942).
Drugs
Administration of LSD was in a single absolute dose of 200 mg,
corresponding to a dose of 2.84 6.13 mg/kg body weight
(mean 6SEM; range, 2.04–3.85 μg). The same dose was used
in LSD-assisted psychotherapy in a clinical study (11). The
dose was within the range of doses taken for recreational
purposes and expected to induce robust effects in humans (1).
The drug preparation is described in Supplement 1.
Study Procedures
The study included a screening visit with the study physician,
a separate psychiatric interview, an additional visit with the
study physician for familiarization, two 25-hour test ses-
sions, and an end-of-study visit. The sessions were con-
ducted in a calm laboratory environment. Only one research
subject and one or two investigators were present during the
test sessions. The test sessions began at 8:15 AM.Aurine
sample was taken to verify abstinence from drugs of abuse,
and a urine pregnancy test was performed in women, and all
subjects underwent baseline measurements. LSD (200 mg) or
placebo was administered at 9:00 AM. The outcome meas-
ures were repeatedly assessed for 24 hours. A standardized
lunch and dinner were served at 1:30 PM and 5:30 PM,
respectively. The subjects were under constant supervision
by the study physician until 1:00 AM. The subjects were never
alone during the first 16 hours after drug administration,
and the investigator was in a room next to the subject for up
to 24 hours. The subjects were sent home the next day at
9:30 AM.
Subjective Drug Effects
Subjective measures included scores on the 5 Dimensions of
Altered States of Consciousness (5D-ASC) scale (29,49),
visual analog scales (VASs) (50), the Adjective Mood Rating
Scale (AMRS) (51), and the Addiction Research Center Inven-
tory (ARCI) (31). The 5D-ASC scale is designed to be used
retrospectively and was administered 24 hours after drug
administration to rate the peak drug effects. The VASs were
administered repeatedly for up to 24 hours to assess drug
effects over time. The AMRS and ARCI were administered
before and 3, 10, and 24 hours after drug administration. The
procedures are described in detail in Supplement 1.
Acoustic Startle Response Measurement
The eye-blink component of the acoustic startle response was
measured using an electromyographic startle system (EMG-
SR-Lab; San Diego Instruments, San Diego, California) as
described in detail elsewhere (36) and in Supplement 1. Briefly,
the session included 16 pulse-alone stimuli (115 dB) and 32
similar pulse trials that were preceded by a 20-msec prepulse
(86 dB) and an interstimulus interval (ISI) of 30, 60, 120, or
2000 msec, resulting in four prepulse trial conditions.
Cardiovascular, Autonomic, Adverse, and Endocrine
Effects
Cardiostimulant (blood pressure and heart rate), autonomic
(body temperature and pupillary function), psychomotor per-
formance, endocrine measures (plasma cortisol, prolactin,
oxytocin, norepinephrine, and epinephrine), and adverse
effects were measured as described in Supplement 1.
Data Analysis
The data were analyzed using STATISTICA Version 12 soft-
ware (StatSoft, Inc, Tulsa, Oklahoma). Peak or peak change
from baseline values were determined for repeated measures.
Data were analyzed using repeated-measures analysis of
variance (ANOVA), with drug (LSD vs. placebo) as the within-
subjects factor. The PPI data were analyzed using repeated-
measures ANOVA, with drug and trial condition (30, 60, 120,
and 2000 msec) as within-subjects factors, followed by direct
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comparisons for each trial condition. Modulatory effects of sex
and hallucinogen experience were evaluated by including the
respective between-subjects factor into the ANOVA. Spear-
man’s rank correlations were used to determine associations
between measures. The criterion for statistical significance
was p,.05.
RESULTS
Subjective Drug Effects
Altered States of Consciousness on the 5D-
ASC. Pronounced alterations of waking consciousness were
induced by LSD (Figure 1). Ratings of oceanic boundlessness
[F
1,15
592.3, p,.001] and visionary restructuralization [F
1,15
5243.5, p,.001] were most strongly increased by LSD. The
elevated ratings for oceanic boundlessness indicated that LSD
elicited a state of positively experienced derealization and
depersonalization with predominantly increased ratings for
“experience of unity”[F
1,15
560.2, p,.001] and “blissful
state”[F
1,15
568.1, p,.001]. Additionally, LSD produced
marked visionary restructuralization phenomena, including
increased ratings for “elementary and complex imagery”
[F
1,15
5123.8, p,.001, and F
1,15
555.9, p,.001,
respectively], “audiovisual synesthesia”[F
1,15
5156.8,
p,.001], and “changed meaning of percepts”[F
1,15
593.3,
p,.001]. Only minimal “auditory alterations”[F
1,15
534.5,
p,.001] were induced by LSD. Also, LSD moderately
increased ratings of anxious ego dissolution [F
1,15
516.1,
p,.01], mostly attributable to significantly increased ratings
for “disembodiment”[F
1,15
534.4, p,.001] and “impaired
control and cognition”[F
1,15
525.3, p,.001], but not
“anxiety”[F
1,15
54.2, p5.06]. Profound anxiety or panic
was not experienced by any subject. However, two subjects
(one woman and one man) reacted with transient anxiety,
including fear of losing control, which completely resolved
without pharmacologic intervention within 2–3 hours. No sex
differences were observed in the effects of LSD on the 5D-
ASC scale.
Psychotropic Effects over Time on VASs. Subjective
effects on the VASs are shown in Figure 2, and maximal
effects are presented in Table S2 in Supplement 1. The
subjective effects began 30–60 min after LSD administration.
Peak effects (any drug effects) were reported after (mean 6
SD) 1.75 6.82 hours. After 5 hours, the subjective effects of
LSD gradually subsided, but effects lasted up to 12 hours after
LSD administration. Three subjects rated the subjective effects
.50% of maximal possible effects at 12 hours. Compared
with placebo, LSD produced pronounced increases in all VAS
ratings, including “any drug effects,”“good drug effect,”“drug
high,”“drug liking,”and “stimulated”[all F
1,15
$1931, all
p,.001]. Peak effects for “any drug effects,”“good drug
effect,”and “drug liking”reached 90% of the maximal
possible score. Additionally, LSD significantly increased rat-
ings of “empathogenic”drug effects, including “happy,”
“closeness,”“open,”and “trust”[all F
1,15
$34, all p,.001].
LSD decreased subjective concentration [F
1,15
5212.5,
p,.001]. Compared with placebo, LSD induced small but
significant increases in “bad drug effect”and “fear”[F
1,15
5
23.9, p,.001, and F
1,15
513.2, p5.003, respectively]. The
subjective effects of LSD did not differ between sexes.
AMRS. On the AMRS, LSD significantly increased ratings
of “well-being”[F
1,15
58.2, p,.05], “emotional excitation”
Figure 1. Effects of lysergic acid
diethylamide (LSD) on the 5 Dimen-
sions of Altered States of Conscious-
ness scale. LSD predominantly
increased ratings of oceanic bound-
lessness and visionary restructuraliza-
tion. Increased oceanic boundlessness
ratings mostly resulted from higher
ratings for blissful state and experience
of unity. Increases in visionary restruc-
turalization ratings were attributable to
high ratings for audiovisual synesthe-
sia, elementary and complex imagery,
and changed meaning of percepts.
LSD produced only very little auditory
alterations. LSD-induced increases in
anxious ego dissolution were small
because of elevated ratings for disem-
bodiment, impaired control, and cog-
nition but not anxiety. Vigilance was
significantly reduced by LSD com-
pared with placebo. The global Altered
States of Consciousness score con-
sists of the summation of the oceanic
boundlessness, anxious ego dissolu-
tion, and visionary restructuralization
scores. **p,.01, ***p,.001 com-
pared with placebo. Data are expres-
sed as mean 6SEM in 16 subjects. AA, auditory alterations; AED, anxious ego dissolution; ASC, Altered States of Consciousness; OB, oceanic boundlessness;
VIR, vigilance; VR, visionary restructuralization.
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[F
1,15
517.4, p,.001], “inactivity”[F
1,15
510.8, p,.01],
“introversion”[F
1,15
516.9, p,.001], and “dreaminess”[F
1,15
557.9, p,.001] compared with placebo (Figure 3 and Table
S2 in Supplement 1). Ratings of “extroversion”or “anxiety”
were not altered by LSD. No sex differences were observed in
the effects of LSD on the AMRS.
ARCI. Subjective effects on the ARCI are presented in Table
S2 and Figure S1 in Supplement 1. LSD significantly increased
ratings on the amphetamine group scale [F
1,15
515.8, p5
.001], with a trend toward significantly reduced ratings on the
benzedrine group scale [F
1,15
53.8, p5.07]. Also, LSD
significantly increased ratings of euphoria and drug liking on
the morphine-benzedrine group scale [F
1,15
531.3, p,.001],
sedation on the pentobarbital-alcohol group scale [F
1,15
5
52.6, p,.001], and ratings on the LSD group scale [F
1,15
5
24.4, p,.001], a measure of dysphoric and psychotomimetic
changes. No sex differences were observed in the effects of
LSD on the ARCI.
Investigator-Rated Drug Effects. The investigator-rated
drug effects are shown in Table S2 and Figure S2 in
Supplement 1. Investigator ratings of “any drug effect”[F
1,15
5449.7, p,.001], “distance from reality”[F
1,15
521.7,
p,.001], “happiness”[F
1,15
537.4, p,.001], and “non-
speech vocalization”[F
1,15
56.9, p,.05] were increased by
LSD. Ratings for “anxiety”or “paranoid thinking”were not
significantly increased. LSD did not alter the percentage of
time “talking with the investigator”compared with placebo.
Acoustic Startle Response
The effects of LSD on PPI and startle response habituation are
shown in Figure 4. The data from one participant were
excluded because of technical reasons. The two-way ANOVA,
with drug and prepulse trial condition as within-subject
factors, revealed a significant drug 3prepulse trial interaction
[F
3,42
53.0, p,.05]. LSD significantly reduced PPI in the 30-
msec and 60-msec trial conditions [F
1,14
55.5, p,.05, and
F
1,14
55.1, p,.05, respectively] and tended to reduce PPI in
the 120-msec trial condition [F
1,14
53.4, p5.09] (Figure 3A).
Compared with placebo, LSD nonsignificantly increased the
startle response (mean reaction amplitude over all pulse-alone
trials [mean 6SD], 571 6321 units and 469 6190 units after
administration of LSD and placebo, respectively). The two-way
ANOVA for pulse-alone trials, with drug and block (time) as
factors, showed a significant main effect of block, indicating
habituation of the startle response over time [F
3,42
512.8,
p,.001]. No drug 3block interaction was observed,
indicating similar habituation of the response over time in the
LSD and placebo conditions (Figure 4B). Similarly, LSD did not
affect percentage of habituation compared with placebo. No
associations were found between percentage of PPI disruption
and any subjective effect ratings assessed shortly before or
after the startle measurement.
Figure 2. Subjective effects of lysergic acid diethylamide (LSD) over time on the visual analog scales. LSD or placebo was administered at t 50 hours. The
subjective effects began 30–60 min after LSD administration, peaked after 1–5 hours, gradually subsided after 5 hours, and were increased up to 12 hours.
LSD produced significant changes in all visual analog scale ratings. However, “bad drug effects”and “fear”were only minimally elevated. LSD also increased
ratings that are typically increased by empathogens, including ratings for “happy,”“closeness,”“open,”and “trust.”Data are expressed as mean 6SEM %
maximal values in 16 subjects.
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Cardiovascular, Autonomic, Adverse, and Endocrine
Effects
Peak values and statistics are shown in Table S2 in
Supplement 1. Compared with placebo, LSD significantly
increased systolic [F
1,15
523.77, p,.001] and diastolic
[F
1,15
525.19, p,.001] blood pressure, heart rate [F
1,15
5
15.27, p5.001], and body temperature [F
1,15
511.61,
p5.004] (Figure 5). LSD significantly increased the pupil size
in the dark and after a light stimulus [F
1,15
522.71 and F
1,15
5
36.33, respectively, both p,.001] (Figure S3 in Supplement 1).
Participants’ability to balance on one foot was significantly
impaired by LSD [F
1,15
526.1, p5.001] (Figure S4 in
Supplement 1). The plasma concentrations of cortisol [F
1,15
5
198.03, p,.001], prolactin [F
1,15
510.13, p,.01], oxytocin
[F
1,15
59.40, p,.01], and epinephrine [F
1,15
58.95, p,.01]
were significantly increased by LSD (Figure 6). Compared with
placebo, LSD significantly increased the total acute (0–10 hours)
[F
1,15
513.67, p,.01] and subacute (10–24 hours) [F
1,15
5
7.19, p,.05] adverse effects but not adverse effects at 24–72
hours. Adverse effects at 24–72 hours did not differ between
LSD and placebo. The frequently reported acute adverse effects
of LSD are presented in Table S3 in Supplement 1. There were
no severe acute effects. The somatic and endocrine effects of
LSD did not differ between sexes.
Figure 3. Subjective effects on the Adjective Mood Rating Scale. Lysergic acid diethylamide (LSD) or placebo was administered at t 50 hours. LSD
induced increases in general well-be ing (A), emotional excitation (B), inactivity (C), introversion (D), and dreaminess (F). LSD did not induce significant anxiety (E).
Data are expressed as mean 6SEM change from baseline in 16 subjects. *p,.05, **p,.01, ***p,.001 compared with placebo.
Figure 4. Effects of lysergic acid
diethylamide (LSD) on the percentage
of prepulse inhibition of the acoustic
startle response (A) and startle
response habituation over time (B).
LSD significantly reduced percentage
of prepulse inhibition in trials with
prepulses that were presented 30
msec or 60 msec before the startle
pulse compared with placebo (A).
A trend toward a significant reduction
of percentage of prepulse inhibition
was observed for the 120-msec pre-
pulse trial condition. LSD did not
significantly alter the startle response
or startle response habituation com-
pared with placebo (B). Data are
expressed as mean 6SEM in 15 subjects. *p,. 05,
(
*
)
p5.09 compared with placebo.
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DISCUSSION
The subjective effects of LSD began 30–60 min after admin-
istration and peaked at 1.75 hours but remained high for 3–5
hours before gradually declining. LSD induced a pronounced
alteration in waking consciousness, including visual percep-
tual alterations, audiovisual synesthesia, and positively expe-
rienced derealization and depersonalization. LSD did not
induce pronounced anxiety and overall produced high ratings
of good drug effects and low ratings of bad drug effects.
Feelings of well-being, happiness, closeness to others, open-
ness, and trust were also increased by LSD, effects typically
associated with the empathogen MDMA (Ecstasy) (52).
The acute psychological effects of LSD lasted 12 hours in
most subjects and up to 16 hours in some, which is longer
Figure 5. Effect of lysergic acid
diethylamide (LSD) on vital signs.
LSD or placebo was administered at
t50 hours. LSD significantly inc-
reased systolic (A) and diastolic (B)
blood pressure, heart rate (C), and
body temperature (D) compared with
placebo. Comparisons for each time
point revealed that the cardiostimu-
lant (A, B) and thermogenic (D)
changes induced by LSD were signif-
icant up to 5 hours after drug admin-
istration compared with placebo, but
moderate trend changes remained up
to 11 hours before the levels returned
to baseline. Data are expressed as
mean 6SEM in 16 subjects. *p,.05,
**p,.01, ***p,.001 compared with
placebo.
Figure 6. Endocrine effects of lysergic acid diethylamide (LSD). LSD significantly increased the plasma concentrations of prolactin (A), cortisol (B),oxytocin(C),
and epinephrine (D). LSD did not significantly alter the plasma levels of norepinephrine (E). LSD or placebo was administered at t 50 min. Data are expressed as
mean 6SEM in 16 subjects. **p,.01, ***p,.001 compared with placebo.
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than the 6–10 hours or 12 hours reported by other authors
(1,17,53); this could be attributable to the relatively high dose
of LSD or more sensitive psychometric measures used in the
present study. The effects of LSD lasted twice as long as the
effects of psilocybin (6 hours) (54,55), lasted longer than the
effects of DMT (,1 hour) (19), and possibly lasted a similar
duration as the effects of mescaline (18,56).
In the present study, LSD produced higher scores on the
5D-ASC scale compared with psilocybin in a similar popula-
tion of healthy subjects (55). In particular, LSD produced 30%
higher ratings for oceanic boundlessness (mostly blissful
state), 30% higher ratings for anxious ego dissolution, and
63% higher ratings for visionary restructuralization (mostly
greater audiovisual synesthesia) compared with a high dose of
psilocybin (55,57). Compared with DMT and ketamine, LSD
produced 50% higher ratings for oceanic boundlessness, 50%
higher ratings for visionary restructuralization, and comparably
high ratings for anxious ego dissolution (22,29). On the AMRS,
LSD produced similar ratings for emotional excitation, inacti-
vation, and dreaminess compared with high-dose psilocybin
(55). Similar to LSD, mean group anxiety scores were not
appreciably increased by psilocybin (55). On the ARCI, LSD
increased ratings on the amphetamine group scale and
morphine-benzedrine group scale, suggesting stimulant and
euphoric subjective effects that were similar to MDMA (58).
In contrast, LSD reduced ratings on the benzedrine group
scale, suggesting reduced energy and focus (58). LSD had
overall similar effects to psilocybin on the ARCI (59). Sub-
jective VAS ratings for happy, open, closeness to others, and
trust were increased by LSD. Similarly, the investigators rated
subjects as being happier after administration of LSD com-
pared with placebo. Similar subjective effects are typically
produced by empathogens, such as MDMA, but not by
stimulants (30,60).
Altogether, the psychometric findings indicate that LSD
produced stronger perceptual alterations than the doses of
other psychotropic drugs tested so far as well as MDMA-like
empathogenic mood effects. Additionally, LSD increased
plasma oxytocin levels. Oxytocin is thought to contribute to
the empathogenic and prosocial effects of MDMA (61) and
may have similar effects in the case of LSD. Although LSD and
MDMA were not compared in the same subjects, the present
findings indicate that LSD exerts partially MDMA-like empa-
thogenic effects that may be associated with common sero-
toninergic or oxytocinergic properties (52). MDMA produces
weak LSD-like perceptual alterations, likely via similar
5-hydroxytryptamine 2A (5-HT
2A
) receptor stimulation (62).
Pharmacologically, LSD acts as a direct partial agonist at
serotoninergic receptors (2,63), whereas MDMA mostly acts
as an indirect serotoninergic agonist by releasing serotonin via
the serotonin transporter (64).
The primary safety concerns with hallucinogen research
are psychological rather than somatic adverse effects (1).
In laboratory studies that use psilocybin, ketamine, or MDMA,
moderate anticipatory anxiety is common at the beginning of
the onset of the drug’s effects (49,65,66). Acute anxiety was
also infrequently reported when LSD was administered at the
same dose as the one used in the present study for LSD-
assisted psychotherapy in patients with anxiety associated
with life-threatening diseases (11). In the present study, LSD
produced anxiety in two subjects, which resolved spontane-
ously with verbal support from the investigators. Anxiety was
related to fear of loss of thought control, disembodiment, and
loss of self as similarly described for psilocybin (55). Some
subjects also had to be reminded of the transient state of the
drug-induced experience. None of the subjects had a current
or past history of major psychiatric disorders, and all were well
informed about the setting and acquainted with and constantly
supervised by the same investigator. Also, only half of the
subjects in the present study were hallucinogen-naïve, and the
other half had very limited prior experience with hallucinogenic
drugs. We found no differences in the quality and extent of the
response to LSD between the hallucinogen-naïve and moder-
ately experienced subjects. Consistent with this finding, prior
experience with hallucinogenic drugs affected the response to
psilocybin only moderately in a similar research setting (66).
In line with our hypothesis, LSD disrupted PPI and pro-
duced sensorimotor deficits similar to deficits observed in
schizophrenia (36–39). In animals, LSD (40–42) and other
serotoninergic hallucinogens (43–45) reduce PPI. Also, LSD
potentiated the startle magnitude and impaired habituation of
the startle response in rats (67). Similar deficits in habituation
were reported in patients with schizophrenia (36,38). Consis-
tent with the preclinical findings, LSD reduced PPI in the
present study at the 30–120 msec ISI. The startle response
amplitude or its habituation was not significantly altered by
LSD. Psilocybin reduced PPI at a short ISI (30 msec), had no
effect at a medium ISI (60 msec), and increased PPI at long
ISIs (120–2000 msec), without changing startle reactivity or
habituation (68,69). The effects of LSD and psilocybin on the
acoustic startle response and its modulation were quite
similar. Additionally, the disruption of PPI induced by psilocy-
bin in humans at a short ISI (30 msec) was prevented by
administration of a 5-HT
2A
receptor antagonist (70), consistent
with similar preclinical studies of LSD (42). In contrast to the
findings with LSD and psilocybin, DMT or ayahuasca had no
effects on PPI, startle reactivity, or habituation in humans
(20,71). Altogether, the effects of LSD on PPI in normal
humans were consistent with the PPI deficits after LSD
administration in animals and sensorimotor gating deficits in
patients with schizophrenia.
Serotoninergic hallucinogens, including LSD, are hypothe-
sized to act at the 5-HT
2A
receptor (2,54), which is upregulated
in patients with schizophrenia (72). Genetic variations in the
5-HT
2A
receptor gene influence PPI (73), and PPI deficits
induced by psilocybin in humans depend on 5-HT
2A
receptor
stimulation (70). In animals, LSD disrupts PPI (40–42) also via
5-HT
2A
receptor stimulation (42). To characterize further the
role of 5-HT
2
receptors and other receptors in the subjective
and sensorimotor psychotomimetic effects of LSD in humans,
future studies should investigate the effects of receptor
antagonists on the response to LSD using a similar exper-
imental setting. The present findings lend support to the use of
LSD to study the neurobiological basis of psychotic states in
humans. To date, brain activation patterns have not been
studied using LSD in neuroimaging studies, in contrast to
several modern investigations that used psilocybin to model
psychotic states (25,26).
Significant sympathomimetic effects, including increases in
blood pressure, heart rate, and pupil size, were produced by
Effects of LSD
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Biological
Psychiatry
LSD. Similar findings were reported in early studies in the
1950s (74–78). In contrast, LSD (200 μg administered orally)
did not alter diastolic or systolic blood pressure or heart rate in
a recent study in eight patients with different chronic life-
threatening illnesses (11). Overall, the cardiostimulant effects
of LSD were moderate and smaller than the effects seen with
empathogens and stimulants (30). The LSD-induced increase
in epinephrine levels in the present study was similar to the
effect produced by MDMA (79).
Body temperature was increased by LSD in the present
study. In animals, LSD is thermogenic (80), and hyperthermia
has been reported to be a consequence of massive LSD
overdose in humans (81). Other serotoninergic hallucinogens,
including psilocybin and DMT, produce similar cardiostimulant
and autonomic responses to LSD (18,55,59,82–84).
In the present study, LSD increased circulating levels of
cortisol and prolactin. LSD binds to dopaminergic D
2
recep-
tors (85). Studies in rats showed that LSD inhibited prolactin
secretion by rat pituitary cells (86) and decreased plasma
levels of prolactin in rats (87). These findings led to the
suggestion that LSD acts as a dopamine D
2
receptor agonist
in the pituitary. However, the present study in humans found
that LSD increased the plasma levels of prolactin and cortisol,
which are markers of serotoninergic activity (88,89). Our
findings suggest that the serotoninergic stimulant effects of
LSD on prolactin regulation usurp any dopamine D
2
receptor–
mediated inhibition in humans at the dose used in the present
study. Other serotoninergic drugs, including psilocybin (55),
DMT (84), ayahuasca (90), and MDMA (30,91), increased the
plasma levels of prolactin and cortisol in humans.
The present study has several limitations. First, we used
only a single dose of LSD, and we cannot provide dose-
response data. We used a relatively high dose of LSD (200 μg),
which produced a full and representative LSD response (1).
The same dose of LSD was also used recently in patients with
anxiety associated with terminal illness (11). Second, although
we used formal blinding, the overt subjective effects of LSD
unblinded the treatment assignment. Additionally, expecta-
tions may have influenced the psychological effects of LSD
because all of the subjects knew that they would receive LSD
or placebo and not another active drug. The psychological
effects and risks of LSD are likely to be different from effects
described herein if LSD is used recreationally in unsupervised
settings or in subjects with psychiatric disorders. Third,
endocrine measures were performed only at two time points
during the expected peak drug effect, not allowing for a full
characterization of the endocrine effects of LSD over a longer
time interval.
In conclusion, LSD produced marked effects on perception
and subjective effects on mood that were similar to effects
reported for MDMA and increased plasma oxytocin, suggest-
ing empathogenic properties that may be useful in psycho-
therapy (11). Consistent with preclinical data and the
sensorimotor deficits seen in schizophrenia, LSD acutely
decreased PPI of the acoustic startle response. The present
experimental human study may serve as an interface for the
translation of preclinical research with hallucinogens to clinical
research findings in patients with schizophrenia and vice
versa. Also, LSD may be useful for further study of alterations
in consciousness and information processing in humans.
The present study showed that LSD can be safely adminis-
tered in an experimental research setting in humans, forming a
basis for further psychopharmacologic studies. However, the
sympathomimetic stimulant effects need to be considered
when LSD is to be used in patients with hypertension or heart
disease.
ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported by the University Hospital Basel, Switzerland, and
the Swiss National Science Foundation Grant No. 320030_1449493.
The authors report no biomedical financial interests or potential conflicts
of interest.
ClinicalTrials.gov: Psychological, Physiological, Endocrine, and Pharma-
cokinetic Effects of LSD in a Controlled Study; http://clinicaltrials.gov/ct2/
show/NCT01878942.
ARTICLE INFORMATION
From Psychopharmacology Research, Clinical Pharmacology and Toxicol-
ogy, Department of Biomedicine and Department of Clinical Research (YS,
FE, MEL), University Hospital Basel, Basel; Private practice for Psychiatry
and Psychotherapy (PG), Solothurn; Biomedicine Service (EG), University
Hospital Lausanne, Lausanne; Neuropsychopharmacology and Brain Imag-
ing and Heffter Research Center, Department of Psychiatry, Psychotherapy
and Psychosomatics (KHP, FXV), University Hospital of Psychiatry Zurich,
Zurich; Department of Clinical Research (RB), University of Bern, Bern; and
Department of Psychiatry (FM, SB), University of Basel, Basel, Switzerland.
Address correspondence to Matthias E. Liechti, M.D., Clinical Pharma-
cology, University Hospital Basel, Hebelstrasse 2, Basel, CH-4031, Switzer-
land; E-mail: matthias.liechti@usb.ch.
Received Sep 30, 2014; revised Oct 28, 2014; accepted Nov 11, 2014.
Supplementary material cited in this article is available online at http://
dx.doi.org/10.1016/j.biopsych.2014.11.015.
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