Review

Cite This: ACS Chem. Neurosci. 2018, 9, 2331−2343 pubs.acs.org/chemneuro

Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide

(LSD)
David E. Nichols*
Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,
United States

ABSTRACT: Lysergic acid diethylamide (LSD) is one of the most potent psychoactive agents known,
producing dramatic alterations of consciousness after submilligram (≥20 μg) oral doses. Following the
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accidental discovery of its potent psychoactive effects in 1943, it was supplied by Sandoz Laboratories
as an experimental drug that might be useful as an adjunct for psychotherapy, or to give psychiatrists
insight into the mental processes in their patients. The finding of serotonin in the mammalian brain in
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1953, and its structural resemblance to LSD, quickly led to ideas that serotonin in the brain might be
involved in mental disorders, initiating rapid research interest in the neurochemistry of serotonin. LSD
proved to be physiologically very safe and nonaddictive, with a very low incidence of adverse events
when used in controlled experiments. Widely hailed by psychiatry as a breakthrough in the 1950s and early 1960s, clinical
research with LSD ended by about 1970, when it was formally placed into Schedule 1 of the Controlled Substances Act of 1970
following its growing popularity as a recreational drug. Within the past 5 years, clinical research with LSD has begun in Europe,
but there has been none in the United States. LSD is proving to be a powerful tool to help understand brain dynamics when
combined with modern brain imaging methods. It remains to be seen whether therapeutic value for LSD can be confirmed in
controlled clinical trials, but promising results have been obtained in small pilot trials of depression, anxiety, and addictions using
psilocybin, a related psychedelic molecule.
KEYWORDS: LSD, lysergic acid diethylamide, Albert Hofmann, hallucinogen, psychedelic, psychotherapy, consciousness,
brain dynamics, mystical experiences, 5-HT2A receptor

■ INTRODUCTION
LSD is the acronym for Lysergsäure Diäthylamid, the German
“A peculiar presentimentthe feeling that this substance
could possess properties other than those established in the
name for lysergic acid diethylamide. LSD is a unique molecule first investigationsinduced me, five years after the first
and has a continuing and rather remarkable history. It was first synthesis, to produce LSD-25 once again so that a sample
could be given to the pharmacological department for further
synthesized in 1938 by Swiss natural products chemist Dr. Albert
tests. This was quite unusual; experimental substances, as a
Hofmann, working in the Sandoz laboratories in Basle, rule, were definitely stricken from the research program if
Switzerland. He synthesized it as the twenty-fifth substance in once found to be lacking in pharmacological interest. In the
a series of lysergic acid derivatives designed to explore possible final step of the synthesis, during the purification and
therapeutic uses of ergot derivatives.1 crystallization of lysergic acid diethylamide in the form of a
Hofmann reports that he had planned the synthesis of LSD tartrate (tartaric acid salt), I was interrupted in my work by
with the intention of obtaining a circulatory and respiratory unusual sensations.”
stimulant because of its structural similarity to nicotinic acid
diethylamide (Coramine), a known analeptic agent. He “Last Friday, April 16, 1943 I was forced to interrupt my work
apparently reasoned that an ergot derivative that incorporated in the laboratory in the middle of the afternoon and proceed
home, being affected by a remarkable restlessness, combined
a diethylamide function might be a potent analeptic agent.
with a slight dizziness. At home I lay down and sank into a
Testing of LSD-25 in the pharmacological department of Sandoz not unpleasant intoxicated-like condition, characterized by an
revealed that it had a strong contractile effect on the uterus. The extremely stimulated imagination. In a dreamlike state, with
research report also noted, in passing, that the mice became eyes closed (I found the daylight to be unpleasantly glaring),
restless after administration of the new drug. Nevertheless, I perceived an uninterrupted stream of fantastic pictures,
the new substance aroused no special interest in the Sandoz extraordinary shapes with intense, kaleidoscopic play of
pharmacologists and physicians so there was no further testing. colors. After some two hours this condition faded away.”
There things remained until April 16, 1943. As Hofmann has
reported:1,2
The following description of this incident comes from the Special Issue: DARK Classics in Chemical Neuroscience
report that Hofmann sent on April 22, 1943 to the Head of Received: January 29, 2018
the Pharmaceutical Department at that time, Professor Arthur Accepted: February 20, 2018
Stoll: Published: February 20, 2018

© 2018 American Chemical Society 2331 DOI: 10.1021/acschemneuro.8b00043

ACS Chem. Neurosci. 2018, 9, 2331−2343
ACS Chemical Neuroscience Review

The extraordinary nature of this mental disturbance led was known that could exert a psychoactive effect after a
Hofmann to suspect that some exogenous compound might be submilligram dose.
responsible. He had been using column chromatography to sep- Professor Rothlin and two of his colleagues then repeated
arate the lysergic acid diethylamide from the epimeric isolysergic Hofmann’s experiment, albeit with only one-third of the dose.
acid diethylamide that resulted from the synthesis and had The effects were still extremely impressive, and validated
prepared the crystalline water-soluble tartrate salt of lysergic acid Hofmann’s observations. Subsequent experiments on volunteer
diethylamide. He concluded that perhaps the lysergic acid colleagues at the Sandoz research laboratories confirmed the
diethylamide that he had been working with that afternoon extraordinary potency of LSD and showed that an oral dose of
somehow could have been responsible. 0.03−0.05 mg of LSD tartrate was effective in humans.
To test that hypothesis, he decided to conduct a self- Hofmann pondered how this substance could have gotten into
experiment with the LSD tartrate. He started with the lowest his body; I personally asked him that question at a meeting more
dose that might have been expected to have any effect, i.e., 0.25 mg. than 20 years ago. He honestly did not know. He was certainly
The notes in his laboratory journal read as follows:2 well aware of the toxic nature of ergot alkaloids, and has reported
“April 19, 1943: Preparation of an 0.5% aqueous solution of that he always maintained very neat work habits. The question
D-lysergic acid diethylamide tartrate. still lacks a good answer, however, as LSD tartrate would not be
4:20 P.M.: 0.5 cc (0.25 mg LSD) ingested orally. The solution is expected to penetrate the skin. It does seem possible, however,
tasteless. that his skin might have contacted a solution of the free base
4:50 P.M.: no trace of any ef fect. during column chromatography, a process he had just completed
5:00 P.M.: slight dizziness, unrest, dif f iculty in concentration, for the purification of the LSD, and the free base could have been
visual disturbances, marked desire to laugh...” absorbed through his skin. Swiss chemists of that era, although
The laboratory notes discontinue at that point, and he reports meticulously neat, rarely, if ever, wore protective gloves.
that the last words were written only with great difficulty.2 He In 1947, the first scientific study was published on the effects of
asked his laboratory assistant to accompany him home, as he LSD.3 (Unless stated otherwise, all references to LSD in this
believed that he might suffer a repetition of the disturbance of the review are to the tartrate of LSD.) In this extensive clinical report,
previous Friday. While cycling home, however, he experienced LSD was administered a total of 49 times; 29 times to 16 normal
much stronger symptoms than the first time. He reports he subjects, and 20 times to six treatment-resistant schizophrenics.
had great difficulty speaking coherently, his field of vision swayed Most doses given to normals were 30 μg, but doses varied for the
before him, and objects appeared distorted, like images in curved schizophrenics, ranging from 20 to 130 μg. The treatment proto-
mirrors. He had the impression of being unable to move from the col was the same for schizophrenics as for normals. The report
spot, although afterward his assistant told him that they had included an extensive table with demographics for the normal
cycled at a good pace. Once at home, his physician was called. subjects, along with their responses to LSD. There was a compre-
By the time the doctor arrived the peak of the crisis had passed. hensive analysis of effects, with very detailed descriptions for five
Hofmann recalls1 that the most outstanding symptoms included: of the normal subjects. In general, the effects started around 30
vertigo, visual disturbances; the faces of those around him appeared min after oral drug administration, reaching a peak about 1.5 h
as grotesque, colored masks; marked motoric unrest, alternating later, maintaining that level of effect for about 2 h, with the
with paralysis; an intermittent heavy feeling in the head, limbs earliest return to normal at about 8 h.
and the entire body, as if they were filled with lead; a dry, In normal subjects, LSD generally produced feelings of
constricted sensation in the throat; and a feeling of choking. He euphoria, visual patterns, feeling young, beautiful, and reborn.
had a clear recognition of his condition, in which state he some- Subjects also reported being more sensitive to music. There was
times observed, in the manner of an independent, neutral less of an effect in schizophrenics than in normals and the authors
observer, that he shouted half insanely or babbled incoherent noted that none of the schizophrenics were made worse by the
words. Occasionally, he says he felt as if he was out of his body. LSD. They also made the first observation of rapid tolerance to
This self-experiment showed that LSD-25 behaved as an the effects of LSD when they administered 100 μg to one subject,
extraordinarily potent psychoactive substance. It also seemed and then gave the same dose the next day, which had no effect.
very significant to Hofmann that he could remember the LSD Considering all the doses they administered, they concluded that
experience in great detail. That meant to him that his “conscious 30 μg was effective, although some subjects received 100 or 130 μg.
recording function” was not interrupted, even at the peak of the The investigators drew parallels to the similarity of effects pro-
LSD experience. For the entire duration of the experiment, duced by mescaline, but emphasized that the very high potency
Hofmann says he had even been aware of participating in an exper- was unique to LSD. They could draw no conclusions about the
iment. “Everything was experienced as completely real, as alarming therapeutic effectiveness of LSD, but strongly encouraged further
reality; alarming, because the picture of the other, familiar clinical research. They also suggested that a radioactive form of
everyday reality was still fully preserved in the memory for LSD might be useful in animal experiments, possibly to deter-
comparison.”1 mine where in the brain the LSD effects originated.
When Hofmann wrote the report to Professor Stoll about his Gion Condrau, working at the same hospital, reported
extraordinary experience with LSD-25, he also sent a copy to the observations from LSD treatment of seven additional normal
director of the pharmacology department, Professor Ernst subjects and 30 treatment-resistant psychiatric patients, with
Rothlin. Not surprisingly, their first reaction was rather incred- similar results.4 Again, psychiatric patients proved more resistant
ulous. A telephone call quickly came; Professor Stoll asked him: than normals to the psychological effects of LSD, even at doses of
“Are you certain you made no mistake in the weighing? Is the 100 μg. They suggested that LSD might eventually find use for
stated dose really correct?” Professor Rothlin also called, asking experimental induction of psychotic states. In a 1949 summary
the same question. Hofmann was certain of that point; he had that included both clinical reports, Stoll reported5 that LSD had
carried out the weighing and dosage himself. They could be by then been administered a total of 240 times; 40 admin-
excused for their doubt because at that time no other substance istrations to 20 healthy volunteers and 200 administrations to
2332 DOI: 10.1021/acschemneuro.8b00043
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ACS Chemical Neuroscience Review

36 patients with psychiatric illness, mostly schizophrenia. In 40 patients given LSD displayed a peculiar disregard for the gravity
administrations of LSD to the healthy volunteers, euphoria and of their situations, and talked freely about their impending death
visual effects were noted. Psychological effects of LSD in psychi- with an affect considered inappropriate in Western culture, but
atric patients were subtle, and not pronounced. most beneficial to their own psychic states. This perspective on
The first Sandoz LSD was brought to the United States for their disease often persisted for periods longer than the analgesic
testing in 1949 by Boston psychiatrist Max Rinkel and Los Angeles action.
psychiatrist Nick Bercel.6,7 Subsequently, Sandoz made LSD-25 This early finding served as the impetus for the use of psyche-
available to research institutes and physicians as an experimental delic therapy in cancer patients at The Maryland Psychiatric
drug, giving it the trade name Delysid (D-Lysergsäure- Research Center in Baltimore, MD from 1963 until 1976, where
Diäthylamid), a name that Hofmann had proposed. 700 patients were treated, mostly with LSD, to relieve their
It is instructive to read the drug label that accompanied inves- anxiety and depression. Their results were generally considered
tigational samples of Sandoz LSD:8 encouraging. This institution was the last to stop its clinical
Indications and dosage research with LSD and related drugs.14
(a) Analytical psychotherapy, to elicit release of repressed material Early on, LSD was widely hailed as a new breakthrough for
and provide mental relaxation, particularly in anxiety states and obses- psychiatry. By 1963, more than 1000 papers had been published
sional neuroses. The initial dose is 25 μg (1/4 of an ampule or 1 tablet). on the effects of LSD in approximately 40,000 humans.15 In 1965
This dose is increased at each treatment by 25 μg until the optimum there were more than 200 research projects in the United States
dose (usually between 50 and 200 μg) is found. The individual using LSD or other psychedelics in human subjects. Unfortu-
treatments are best given at intervals of 1 week. nately, despite such high enthusiasm, the relatively rudimentary
(b) Experimental studies on the nature of psychoses: By taking clinical instruments, lack of controls, and poor follow-up used in
Delysid himself, the psychiatrist is able to gain an insight into the those early clinical studies often led to inconclusive results, and it
world of ideas and sensations of mental patients. Delysid can also be was difficult to assess whether LSD had any real therapeutic
used to induce model psychoses of short duration in normal subjects, value. For example, one popular treatment of the time was the
thus facilitating studies on the pathogenesis of mental disease. In use of LSD in a program of therapy for alcoholism. Until very
normal subjects, doses of 25 to 75 μg are generally suf f icient to recently, it had been widely assumed that this therapy was
produce a hallucinatory psychosis (on an average 1 μg/kg body ineffective. Yet in a recent meta-analysis in a pooled analysis of six
weight). In certain forms of psychosis and in chronic alcoholism, early randomized controlled clinical trials, Krebs and Johansen
higher doses are necessary (2 to 4 μg/kg body weight). found that a single dose of LSD had a significant beneficial effect
There were two different approaches to psychotherapy with on alcohol misuse at the first reported follow-up assessment,
LSD: “psycholytic” and “psychedelic”.9,10 The psycholytic which ranged from 1 to 12 months after discharge from each
approach was more commonly employed in Europe, whereas treatment program.16 They report that the treatment effect of LSD
psychedelic therapy had its origin in Canada. Psycholytic therapy on alcohol misuse was seen at 2 to 3 months and at 6 months, but
involved administering 50−200 μg of LSD to patients once or was not statistically significant at 12 months post-treatment.
twice a week just prior to psychotherapy. The dosage was indi- They note that the effectiveness of a single dose of LSD com-
vidually adjusted so that the patient remained oriented and in pared well with the effectiveness of daily naltrexone,
communication with the therapist, and able to realize the thera- acamprosate, or disulfiram.
peutic character of the situation. The patient lay on a couch in a With the passage of the Controlled Substances Act (CSA) of
darkened room with one attendant (usually a specially trained 1970, LSD was placed in the most restrictive category of drugs,
nurse) and was occasionally visited by the physician. The drug- Schedule 1, where it was classified to have a high potential for
induced experience played only a supporting role in a primarily abuse, no recognized medical use, and no safety when used by a
conventional psychoanalytical treatment, because low dose LSD physician. There were other factors that contributed to the end of
was believed to facilitate the recall of unconscious material. clinical research with LSD, but 1970 is considered the date when
Typically, treatment continued for months to years, with LSD research essentially stopped. Bonson17 has written a
between 10 and 50 psycholytic sessions being conducted.10 fascinating regulatory history of LSD that goes into some detail
A second treatment approach was known as psychedelic regarding the end of approved LSD research. With that, clinical
therapy, and was originally developed primarily for the treatment research with LSD stopped for nearly four decades.
of alcoholics, addicts, and those with personality problems.11 Renewed Clinical Research Interest in LSD. Liechti18 has
This procedure made induction of mystic/religious experiences reviewed all of the clinical studies that employed LSD in the last
the basis of its therapeutic action. It used a quasi-religious prep- 25 years. He has summarized the general findings of those
aration of the patient, higher doses, specific surroundings, and studies, but the most recent results will be briefly highlighted in
music to favor evocation of deep-reaching insights and religious this review. Generally, in a controlled setting, LSD acutely induces
experiences. With this approach, patients underwent daily psycho- bliss, audiovisual synesthesia, altered meaning of perceptions,
therapy for weeks prior to a single high dose administration of LSD, derealization, depersonalization, and mystical experiences. In sev-
typically 400 μg or more, to ensure an overwhelming tran- eral studies, blockade of the subjective effects of LSD following oral
scendental experience. The drug session might typically last from administration of the 5-HT2A-selective antagonist ketanserin
12 to 16 h. demonstrated that the subjective effects of LSD were mediated
One other type of therapy from that era also should be by the 5-HT2A receptor. LSD also increased feelings of closeness to
mentioned. In 1962, Eric Kast, an Assistant Professor of Medicine others, openness, trust, and suggestibility, impaired the recognition
and Psychiatry in Chicago, compared the analgesic action of of sad and fearful faces, reduced left amygdala reactivity to fearful
dihydromorphinone and meperidine (Demerol) with LSD in a faces, and enhanced emotional empathy. Interestingly, LSD
double-blind study with 50 gravely ill patients.12,13 When com- increased the emotional response to music and the meaning of
pared with LSD, both opioid drugs were inferior in their analgesic music, providing a scientific basis for the widespread subjective
action. In addition to pain relief, however, it was noted that the impression that psychedelics improve appreciation of music.
2333 DOI: 10.1021/acschemneuro.8b00043
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Resting-state functional magnetic resonance imaging studies have emotions “wonder,” “transcendence,” “power,” and “tenderness.”
shown that LSD acutely reduces the integrity of functional brain The authors conclude that their “findings reinforce the long-held
networks and increases connectivity between networks that nor- belief that psychedelics enhance music-evoked emotion, and
mally are more dissociated. LSD increases functional thalamocort- provide tentative and indirect support for the notion that this
ical connectivity and functional connectivity of the primary visual effect can be harnessed in the context of psychedelic-assisted
cortex with other brain areas, an effect that is correlated with psychotherapy.”
subjective hallucinations. Acutely, LSD-induced global increases in In a second study, Kaelen et al.22 investigated the interaction
brain entropy were associated with greater trait openness 14 days between LSD and music-listening on eyes-closed imagery using a
later. In patients with anxiety associated with life-threatening placebo-controlled, functional magnetic resonance imaging
disease, anxiety was reduced for two months after two doses (fMRI) approach. Twelve healthy volunteers received 75 μg of
of LSD. intravenously administered LSD free base, and on a separate
There has been only one recent clinical trial of LSD where a occasion, placebo, before being scanned under eyes-closed rest-
potential therapeutic outcome was the goal. Gasser et al.19 ing conditions with and without music-listening. The para-
reported on a double-blind, randomized, active placebo- hippocampal cortex (PHC) had previously been linked with
controlled pilot study to examine safety and efficacy of LSD- music-evoked emotion, the action of psychedelics, and mental
assisted psychotherapy in 12 patients with anxiety associated imagery. Their imaging analyses thus focused on changes in the
with life-threatening diseases. The participants received either connectivity profile of the PHC. Results revealed increased func-
200 μg of LSD (free base) (n = 8) or 20 μg of LSD as an active tional connectivity between the PHC-visual cortex (VC) and
placebo, with an open-label crossover to 200 μg of LSD after the PHC to VC information flow in the interaction between music
initial blinded treatment was unmasked (n = 4). At 2 month and LSD. This latter result positively correlated with ratings of
follow-up, positive trends were found on the State-Trait Anxiety enhanced eyes-closed visual imagery, including imagery of an
Inventory (STAI) in reductions in trait anxiety (p = 0.033) with autobiographical nature. Their findings suggest a possible mech-
an effect size of 1.1, and state anxiety was significantly reduced anism by which LSD works in combination with music to
(p = 0.021), with an effect size of 1.2. No acute or chronic adverse enhance certain subjective experiences that may be useful in a
effects persisted beyond the day after treatment. They conclude therapeutic context.
that LSD can reduce anxiety when administered in a Barrett et al.23 analyzed the blood oxygen level-dependent
methodologically rigorous medically supervised psychothera- (BOLD) signal during music listening in 25 healthy adults after
peutic setting. administration of placebo, LSD (100 μg free base), and LSD
In a one year follow up to their study, Gasser et al.20 reported following pretreatment with the 5HT2A antagonist ketanserin.
that the significant benefits measured with the STAI were They carried out a secondary analysis of data published by Preller
sustained over a 12 month period. From a Qualitative Content et al.24 Tonality-tracking analysis of BOLD data revealed that
Analysis (QCA), participants consistently reported insightful, 5HT2A receptor signaling alters the neural response to music in
cathartic, and interpersonal experiences, accompanied by a brain regions supporting basic and higher-level musical and
reduction in anxiety (77.8%) and an increase in quality of life auditory processing, and areas involved in memory, emotion, and
(66.7%). Evaluations of subjective experiences suggested facil- self-referential processing. Their finding suggests a critical role of
itated access to emotions, confrontation of previously unknown 5HT2A receptor signaling in the neural tracking of dynamic tonal
anxieties, worries, resources, and intense emotional peak expe- structure in music, as well as in supporting the associated increases
riences as major psychological working mechanisms. The expe- in emotionality, connectedness, and meaningfulness in response
riences led to a restructuring of the person’s emotional trust, to music that are commonly observed after LSD.
situational understanding, habits, and worldview. The effect of LSD on suggestibility also has recently been
Although there has been only one recent therapeutic trial of studied. Carhart-Harris et al.25 administered intravenous LSD
LSD, the drug now has been used in a variety of clinical research (40−80 μg; free base) to 10 healthy volunteers in a within-
studies designed to understand how LSD affects emotion or subject placebo-controlled design. The investigators assessed
affect, or to understand the basic brain pharmacology/physiology suggestibility and cued mental imagery using the Creative Imag-
that leads to its unique effects. For example, clinical applications ination Scale (CIS) and a mental imagery test (MIT). CIS and
of psychedelics usually include listening to music during the MIT items were split into two versions (A and B), balanced for
acute drug effects. Indeed, music is thought to be an important “efficacy” (i.e., A ≈ B), and counterbalanced across conditions
element in psychedelic-assisted psychotherapy, yet no one had (i.e., 50% completed version “A” under LSD). The MIT and CIS
provided a scientific basis for this belief. In the past few years, were given at 110 and 140 min, respectively, postinfusion, corre-
however, research has been carried out to study the effect of sponding to the peak drug effects. Volunteers gave significantly
music on the altered state of consciousness produced by LSD or higher ratings for the CIS (p = 0.018), but not the MIT (p = 0.11),
other psychedelics. In the first of these studies, Kaelen et al.21 after LSD, compared to placebo. The magnitude of suggestibility
sought to test the hypothesis that music-evoked emotions are enhancement under LSD was positively correlated with baseline
enhanced under LSD. Ten healthy volunteers were recruited trait conscientiousness (p = 0.0005). Their findings imply that
who listened to five different tracks of instrumental music during LSD enhances the influence of suggestion. The ability of LSD to
each of two study days, a placebo day followed by an LSD day, enhance suggestibility may have implications for its use as an
separated by 5−7 days. The dosage of LSD (free base) varied adjunct to psychotherapy, where suggestibility plays a major role.
among participants: one received 40 μg, two 50 μg, six 70 μg, and The inability of LSD to affect cued imagery implies that sug-
one 80 μg. Subjective ratings completed after each music track gestions must be of a sufficient duration and level of detail to be
included a visual analogue scale (VAS) and the nine-item Geneva enhanced by the drug.
Emotional Music Scale (GEMS-9). Based on results using these Although LSD is well-known to induce perceptual alterations,
instruments, the authors were able to demonstrate that LSD it was not known whether LSD could alter emotional processing
enhances the emotional response to music, especially the in ways that would support psychotherapy. Dolder et al.26
2334 DOI: 10.1021/acschemneuro.8b00043
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ACS Chemical Neuroscience Review

investigated the acute effects of LSD on emotional processing and LSD together with the 5-HT2A receptor antagonist
using the Face Emotion Recognition Task (FERT) and Multi- ketanserin (40 mg orally). A standardized formal measure of
faceted Empathy Test (MET). The Social Value Orientation dream mentation was used to quantitate cognitive bizarreness of
(SVO) test was used to test the effects of LSD on social behavior. guided mental imagery reports. The state of consciousness was
Two similar placebo-controlled, double-blind, randomized, evaluated using the Altered State of Consciousness (5D-ASC)
crossover studies were conducted using 100 μg of oral LSD questionnaire. Compared with placebo, LSD significantly
in 24 subjects and 200 μg of oral LSD (free base) in 16 subjects. increased cognitive bizarreness (p < 0.001). The LSD-induced
All of the subjects were healthy and most were hallucinogen- increase in cognitive bizarreness was positively correlated with
naive 25−65 year old volunteers (20 men, 20 women). LSD the LSD-induced loss of self-boundaries and cognitive control
produced feelings of happiness, trust, closeness to others, (p < 0.05). Ketanserin fully blocked both LSD-induced increases
enhanced explicit and implicit emotional empathy on the in cognitive bizarreness and changes in state of consciousness.
MET, and impaired the recognition of sad and fearful faces on Thus, LSD produced mental imagery similar to dreaming, pri-
the FERT. LSD enhanced participants’ desire to be with other marily through activation of the 5-HT2A receptor and in relation
people and increased their prosocial behavior on the SVO test. to loss of self-boundaries and cognitive control.
The investigators suggest that these effects of LSD on emotion Kraehenmann et al.30 tested the hypotheses that LSD increases
processing and sociality may be useful for LSD-assisted primary process thinking and that primary process thinking
psychotherapy. depends on 5-HT2A receptor activation and is related to subjec-
It has been proposed that, with eyes-closed under psy- tive drug effects. Twenty-five healthy subjects performed an
chedelics, the brain may function as if there is visual input when audio-recorded mental imagery task 7 h after drug administration
there is none. Roseman et al.27 tested this hypothesis, analyzing during three drug conditions: placebo, LSD (100 μg orally) and
resting-state functional connectivity (RSFC) data from 10 healthy LSD together with the 5-HT2A receptor antagonist ketanserin
subjects under the influence of LSD and, separately, placebo. The (40 mg orally). The main outcome variable in this study was
investigators suspected that eyes-closed psychedelic imagery primary index (PI), a formal measure of primary process thinking
might involve transient local retinotopic activation, of the sort in the imagery reports. State of consciousness was evaluated
typically associated with visual stimulation. It was hypothesized using the 5D-ASC rating scale. LSD, compared with placebo,
that, under LSD, patches of the visual cortex with congruent significantly increased primary index. The LSD-induced increase
retinotopic representations would show greater RSFC than in primary index was positively correlated with LSD-induced
incongruent patches. During the nondrug baseline condition, a disembodiment, and blissful state on the 5D-ASC. Ketanserin
retinotopic localizer was used to identify nonadjacent patches of fully blocked both LSD-induced increases in primary index and
visual cortex V1 and V3 that represent the vertical or the changes in state of consciousness. Thus, LSD induces primary
horizontal meridians of the visual field. Subsequently, RSFC process thinking through activation of 5-HT2A receptors and in
between V1 and V3 was measured with respect to these a priori relation to disembodiment and blissful state. Primary process
identified patches. Consistent with the investigators’ hypothesis, thinking appears to organize inner experiences crucially during
the difference between RSFC of patches with congruent both dreams and psychedelic states of consciousness.
retinotopic specificity (horizontal−horizontal and vertical− To study LSD-induced mystical experiences, Liechti et al.31
vertical) and those with incongruent specificity (horizontal− conducted two placebo-controlled, double-blind, crossover
vertical and vertical−horizontal) increased significantly under studies using oral administration of 100 and 200 μgof LSD free
LSD relative to placebo. Their finding suggests that activity base in 24 and 16 subjects, respectively. Acute effects of LSD
within the visual cortex becomes more dependent on its intrinsic were assessed using the 5D-ASC scale after both doses, and the
retinotopic organization in the drug condition. This result may Mystical Experience Questionnaire (MEQ) only after 200 μg.
indicate that under LSD, with eyes-closed, the early visual system On the MEQ, 200 μg of LSD induced mystical experiences that
behaves as if it were seeing spatially localized visual inputs. were comparable to those in patients who underwent LSD-
Terhune et al.28 investigated the impact of LSD on color assisted psychotherapy. On the 5D-ASC scale, LSD produced
experiences in response to standardized graphemes and sounds higher ratings of blissful state, insightfulness, and changed mean-
and the consistency and specificity of grapheme- and sound-color ing of percepts after 200 μg compared with 100 μg. Plasma levels
associations. The design was within-groups and placebo- of LSD were not positively correlated with its effects, with the
controlled. Participants reported more spontaneous synesthe- exception of ego dissolution at 100 μg. LSD may produce greater
sia-like experiences under LSD, relative to placebo, but did not or different alterations of consciousness at 200 μg (i.e., a dose
differ across conditions in color experiences in response to that is currently used in psychotherapy in Switzerland) compared
inducers, consistency of stimulus-color associations, or inducer with 100 μg (i.e., a dose used in imaging studies). Ego dissolution
specificity. Further analyses suggested that individual differences may reflect plasma levels of LSD, whereas more robustly induced
in a number of these effects were associated with the propensity effects of LSD may not result in such associations.
to experience states of absorption in one’s daily life. Their Recent studies of psychedelics have incorporated modern
preliminary results suggest that LSD-induced synesthesia-like brain imaging techniques to reveal important information about
experiences do not exhibit consistency or inducer-specificity and brain dynamics and functional connectivity. The use of psyche-
thus do not meet two widely established criteria for genuine delics as tools to study brain function has proven to be partic-
synesthesia. ularly important. Tagliazucchi et al.32 studied the effects of LSD
Kraehenmann et al.29 tested the hypotheses that LSD pro- on intrinsic functional connectivity within the human brain using
duces dreamlike waking imagery that depends on 5-HT2A fMRI. High-level association cortices (partially overlapping with
receptor activation, and is related to subjective drug effects. the default-mode, salience, and frontoparietal attention net-
Twenty-five healthy subjects performed an audio recorded works) and the thalamus showed increased global connectivity
guided mental imagery task 7 h after drug administration during under LSD. The cortical areas showing increased global connec-
three drug conditions: placebo, LSD (100 μg of free base orally), tivity overlapped significantly with a map of 5-HT2A receptor
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densities. LSD also increased global integration by increasing the which might subsequently promote the formation of LSD-
level of communication between normally distinct brain net- induced visual images.
works. The increase in global connectivity observed with LSD It has been proposed that the thalamocortical system is an
correlated with subjective reports of “ego dissolution.” These important site of action for hallucinogenic drugs and an essential
results provided the first evidence that LSD selectively expands component of the neural correlates of consciousness. Muller et al.36
global connectivity in the brain, compromising the brain’s mod- orally administrated 100 μg of LSD free base to 20 healthy
ular organization and, simultaneously, the perceptual boundaries participants prior to fMRI assessment. Whole brain thalamic
between the self-and the environment. functional connectivity was measured using ROI-to-ROI and
Carhart-Harris et al.33 employed three complementary ROI-to-voxel approaches. Relationships between thalamic connec-
neuroimaging techniques: arterial spin labeling (ASL), BOLD tivity to regions involved in auditory and visual hallucinations and
measures, and magnetoencephalography (MEG), implemented subjective ratings on auditory and visual drug effects were
during resting state conditions. These studies revealed marked explored using correlation analyses. LSD caused significant alter-
changes in brain activity after LSD that correlated strongly with ations in all dimensions of the 5D-ASC scale and significantly
its psychological effects. Visual cortex cerebral blood flow (CBF) increased thalamic functional connectivity to various cortical
was increased, with decreased visual cortex alpha power, and a regions. In addition, LSD-induced functional connectivity mea-
greatly expanded primary visual cortex (V1) functional sures between the thalamus and the right fusiform gyrus and
connectivity profile, all of which correlated strongly with ratings insula correlated significantly with subjective auditory and visual
of visual hallucinations, indicating that intrinsic brain activity drug effects. Hallucinogenic drug effects thus might be induced
exerts greater influence on visual processing in the psychedelic by facilitations of cortical excitability via thalamocortical
state. Surprisingly, the marked effects of LSD on the visual cortex interactions.
did not significantly correlate with the drug’s other characteristic Mueller et al.37 used functional magnetic resonance imaging
effects on consciousness. Instead, decreased connectivity (fMRI) to investigate the acute effects of LSD on the neural
between the parahippocampus and retrosplenial cortex (RSC) substrate of emotional processing in humans. Using a double-
correlated strongly with ratings of “ego-dissolution” and “altered blind, randomized, crossover study design, placebo or 100 μg of
meaning,” suggesting the importance of this particular circuit for LSD free base was orally administered to 20 healthy subjects
the maintenance of “self” or “ego” and its processing of “meaning.” before the fMRI scan, taking into account the subjective and
Strong relationships also were found between the different pharmacological peak effects of LSD. The plasma levels of LSD
imaging metrics, enabling firmer inferences to be made about were determined immediately before and after the scan. The
their functional significance. administration of LSD significantly reduced reactivity of the left
Timmermann et al.34 presented an auditory oddball paradigm amygdala and the right medial prefrontal cortex relative to
to 20 healthy participants (16 males, 4 female) under LSD and placebo during the presentation of fearful faces. The investigators
placebo conditions, and recorded brain activity using MEG. Scalp noted a significant negative correlation between LSD-induced
level Event Related Fields (ERF) revealed reduced neural adap- amygdala response to fearful stimuli and the LSD-induced sub-
tation to familiar stimuli, and a blunted neural “surprise” jective drug effects. Their data suggest that acute administration
response to novel stimuli in the LSD condition. Dynamic causal of LSD modulates the engagement of brain regions that mediate
modeling revealed that both the presentation of novel stimuli and emotional processing.
LSD modulate backward extrinsic connectivity within a task- Despite their clinical relevance, the neurochemical and anat-
activated fronto-temporal network, as well as intrinsic connectivity omical substrates enabling meaningful experiences are largely
in the primary auditory cortex. These findings suggest that, rather unknown. Therefore, Preller et al.24 investigated the neuro-
than being a marker of conscious level per se, backward connec- pharmacology of personal relevance processing in humans by
tivity may index modulations of perceptual learning common to a combining fMRI and the administration of LSD, well-known to
variety of altered states of consciousness, perhaps united by a alter the subjective meaning of percepts, with and without pre-
shared altered sensitivity to environmental stimuli. treatment with the 5-HT2A-selective receptor antagonist
Schmidt et al.35 explored the effect of 5-HT2A receptor acti- ketanserin. Ketanserin fully blocked general subjective LSD
vation on response inhibition neural networks in healthy subjects effects. Further, ketanserin inhibited the LSD-induced attribu-
given LSD, and further tested whether brain activation during tion of personal relevance to previously meaningless stimuli and
response inhibition under LSD exposure was related to LSD- modulated the processing of meaningful stimuli in cortical
induced visual hallucinations. In a double-blind, randomized, midline structures. These findings point to the essential role of
placebo-controlled, crossover study, LSD (100 μg of free base) the 5-HT2A receptor subtype and cortical midline regions in the
and placebo were administered to 18 healthy subjects. Functional generation and attribution of personal relevance.
magnetic resonance imaging was used to assess response inhi- Personality is known to be relatively stable throughout
bition in a Go/No-Go task. Relative to placebo, LSD admin- adulthood. Nonetheless, it has been shown that major life events
istration impaired inhibitory performance and reduced brain with high personal significance, including experiences engendered
activation in the right middle temporal gyrus, superior/middle/ by psychedelic drugs, can have an enduring impact on some core
inferior frontal gyrus and anterior cingulate cortex and in the left facets of personality. Using a balanced-order, placebo-controlled
superior frontal and postcentral gyrus and cerebellum. Para- study, Lebedev et al.38 investigated biological predictors of post-
hippocampal activation during response inhibition was differ- LSD changes in personality. Nineteen healthy adults were
ently related to inhibitory performance after placebo and LSD administered resting state fMRI scans under LSD (75 μg, I.V.)
administration. Finally, activation in the left superior frontal and placebo (saline I.V.). Participants completed the Revised
gyrus under LSD was negatively related to LSD-induced NEO Personality Inventory at screening and 2 weeks after LSD/
cognitive impairments and visual imagery. Their findings show placebo. Scanning sessions consisted of three 7.5 min eyes-closed
that 5-HT2A receptor activation by LSD leads to a hippocampal- resting-state scans, one of which involved music listening.
prefrontal cortex-mediated breakdown of inhibitory processing, Measures of sample entropy were extracted using a standardized
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Scheme 1. First Synthesis of LSD, reported by Stoll and Hofmann in 194340

preprocessing pipeline, which characterizes the predictability of It now should be evident that earlier ideas that psychedelics
an fMRI time-series. Mixed-effects models were used to evaluate “expanded consciousness” were not far from the mark. Further,
drug-induced shifts in brain entropy and their relationship with the class name psychedelics, which essentially means “mind
the observed increases in the personality trait openness at the manifesting,” is probably the best name for this class, despite the
two-week follow-up. Globally, LSD had a pronounced effect on fact that “hallucinogen” continues to be the legal classification for
brain entropy, increasing it in both sensory and hierarchically these substances.
higher networks across multiple time scales. These shifts pre- Properties and Chemical Synthesis. (5R,8R)-9,10-
dicted enduring increases in trait openness. In addition, the Didehydro-N,N-diethyl-6-methylergoline-8β-carboxamide
predictive power of the entropy increases was greatest for the (N,N-diethyl lysergamide; d-lysergic acid diethylamide; Lyser-
music-listening scans and when “ego-dissolution” was reported gide; LSD-25; Delysid) C20H25N3 (323.42). The free base has
during the acute experience. These results shed new light on how mp 83 °C after recrystallization from benzene and [α]D +30
LSD-induced shifts in brain dynamics and concomitant (c = 0.44, pyridine).40 Two molecules of LSD base form a
subjective experience might be predictive of lasting changes in crystalline salt with one molecule of D-tartaric acid that includes
personality. It also seems likely that increased openness would be two molecules of MeOH and has mp 198−200 °C and [α]D +30
very useful for psychotherapeutic interventions. (c = 1, H2O).41 The pKa of LSD is reported as 7.8.42
As can be seen from the above discussion, recent studies have The first synthesis of lysergic acid N,N-diethylamide (LSD,
begun to elucidate the effects of LSD on the human brain, but the LSD-25) was reported by Stoll and Hofmann in 1943,40 and is
underlying dynamics certainly are not yet completely under- illustrated in Scheme 1. Ergotamine, or another peptide ergot
stood. Atasoy et al.39 very recently used “connectome-harmonic alkaloid, was heated with anhydrous hydrazine to produce
decomposition,” a novel method to investigate dynamical racemic isolysergic acid hydrazide. This process racemizes the
changes in brain states after LSD. They found that LSD alters lysergic acid nucleus at C(5) and also epimerizes the carboxylic
the energy and the power of individual harmonic brain states in a acid moiety at C(8). The d-and l-isolysergic acid hydrazides thus
frequency-selective manner. Remarkably, that led to an expan- obtained were then chemically resolved using d- or l-di(p-toluyl)-
sion of the repertoire of active brain states, indicating a general tartaric acids. The resolved d-isolysergic acid hydrazide was then
reorganization of brain dynamics given the nonrandom increase treated with ethanolic KOH to epimerize the C(8) position and
in coactivation across frequencies. Interestingly, they observed afford d-lysergic acid hydrazide. This hydrazide was then treated
that the frequency distribution of the active repertoire of brain with nitrous acid to afford the corresponding lysergic acid azide,
states under LSD closely follows power-laws, indicating a reor- which was layered over with a cold diethyl ether solution of
ganization of the dynamics at the edge of criticality. A natural diethylamine, whereupon the diethyl group attacked and
functional consequence of tuning brain dynamics toward replaced the azide. The d-lysergic acid N,N-diethylamide thus
criticality, as was observed under LSD, is an increased sensitivity obtained was then crystallized as the natural tartrate salt.
to both internal intrinsic activity, as well as external stimuli, which In 1966, U.S. patent 3,239,530 was awarded to Hofmann and
in turn leads to greater sensitivity to both the internal milieu and his Sandoz co-workers for an improved method of preparing
the external environment, referred to as “set” and “setting,” optically active isolysergic acid hydrazides that avoided race-
respectively, in relation to psychedelics. The expanded repertoire mization at carbon 5.43 Adding 1 equiv of a strong acid for each
of brain states and increase in cross-frequency correlations under equivalent of ergot alkaloid, followed by heating with anhydrous
LSD demonstrate that more brain states contribute to neural hydrazine, resulted predominantly in the formation of (+)-(5R)-
activity under LSD, leading to a richer, more flexible repertoire of isolysergic acid hydrazide, with no racemization at C(5). This
dynamics. The fact that their coactivation patterns also are highly hydrazide was then carried forward as indicated in Scheme 1.
correlated over time indicates a preserved stability in brain More efficient methods were subsequently developed using
dynamics, albeit a “stability” of a different kind with more lysergic acid that had been obtained by alkaline hydrolysis of
complex dynamics. ergot alkaloids, e.g. ergotamine. These methods largely
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Figure 1. Structures of identified LSD metabolites.

minimized epimerization at C8. Typically, the carboxylic acid for 24 h and feces for 48 h. Axelrod et al.53 found less than 1% of
function of lysergic acid was activated for nucleophilic attack. the administered LSD in urine or feces, and concluded that LSD
A very early example includes activation of the carboxylic acid underwent almost complete metabolic transformation in
function with carbonyl diimidazole, followed by treatment with monkeys. In later studies using rat liver microsomes, Niwaguchi
diethylamine.44 Formation of the mixed anhydride with et al.55,56 identified lysergic acid monoethylamide (LAE) (which
trifluoroacetic acid also has been reported, followed by reaction originates from enzymatic N-dealkylation of the diethylamide
with diethylamine.45 These methods gave good yields but moiety), and nor-LSD, by N(6)-demethylation of LSD.
required the use of anhydrous lysergic acid, which demanded In animals, metabolism of LSD is highly species dependent,
vacuum drying. Another method that gave excellent yields but generally seems to follow several pathways. Aromatic hydrox-
involved treatment of the lithium salt of lysergic acid with a ylation leads to 13- and 14-hydroxy LSD, which are primarily
solution of SO3 in DMF, followed by treatment with diethyl- excreted as glucuronides.57 Metabolites are secreted in the bile
amine.46 This synthesis was the one used to make large quantities and excreted via the gut, with negligible amounts of unchanged
of “black market” LSD during the 1960s.47 Obviously, great care drug found in feces or urine.
has to be taken when using a solution of SO3. One of the simplest [14C]-LSD is almost completely metabolized by rats, guinea
syntheses was reported by Johnson et al.48 This method was pigs, and rhesus monkeys,58 with only very little of the unchanged
applicable to preparation of a variety of lysergamides using drug excreted. The elimination of [14C]-LSD in the rat, guinea
lysergic acid hydrate when the appropriate primary or secondary pig, and rhesus monkey over a 96 h period was investigated by
amine was readily available.49 The reaction is rapid and is carried Siddik et al.58 Rats (1 mg/kg i.p.) excreted 73% of the 14C in
out in CHCl3 at reflux with POCl3 as the condensing agent. All feces, 16% in urine, and 3.4% in the expired air as 14CO2. Guinea
syntheses of LSD typically required a final purification by column pigs (1 mg/kg i.p.) excreted 40% in feces, 28% in urine, and 18%
chromatography over alumina, where the normal lysergic acid as expired 14CO2. Rhesus monkeys (0.15 mg/kg i.m.) eliminated
diethylamide elutes from the column first as a bright blue 23% in the feces and 39% in the urine.
fluorescent band under long wave UV. The major metabolites in rats and guinea pigs (urine and bile)
A recent very useful synthesis employs (benzotriazol-1- were glucuronic acid conjugates of 13- and 14-hydroxy-LSD.
yloxy)tripyrrolidinophosphonium hexafluorophosphate guinea pigs excreted significant amounts of 2-oxo-LSD in urine
(PyBOP),50 a crystalline and stable peptide condensing agent and bile. Lysergic acid ethylamide (LAE) was a minor urinary
that readily couples lysergic acid with amines. It can be especially metabolite in both species. In rat livers perfused with [14C]-LSD,
useful when the amine is the limiting reagent.51,52 This synthesis Siddik et al.59 identified the glucuronides of 13- and 14-hydroxy-
is carried out at room temperature in CH2Cl2 and proceeds very LSD, as well as 2-oxo-LSD, LAE, and nor-LSD.
rapidly with no epimerization at C8. This method also is scalable, LSD had a unique metabolic profile in rhesus monkeys. Their
but as in other preparations, the crude amide requires chro- urine contained at least nine metabolites. Four of them were iden-
matography to obtain pure product. tified as 13- and 14-hydroxy-LSD (as glucuronic acid conjugates),
Drug Metabolism. LSD is rapidly absorbed from the gut LAE, and a naphthostyril derivative. Glucuronic acid conjugates
after oral administration and is almost completely metabolized, of 13- and 14-hydroxy-LSD were present in only small amounts
primarily by the liver. It was first established by Axelrod in 1957, in rhesus monkeys, setting them apart from rats and guinea pigs.
using in vitro studies, that LSD is metabolized by NADH- Klette et al.60 have reported that in 144 human urine spec-
dependent microsomal liver enzymes from the guinea pig to the imens of subjects who had taken LSD, 2-oxo-3-OH-LSD
inactive 2-oxo-LSD and 2-oxo-3-hydroxy LSD (Figure 1).53,54 In was found in every specimen studied (n = 144) at a mean con-
Rhesus monkeys given 0.2 mg/kg LSD i.v., urine was collected centration 16−43 times higher than the parent LSD.
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These investigators studied Phase I drug metabolism of LSD by The subjective effects lasted (mean ± SD) 8.2 ± 2.1 and 11.6 ±
incubating human liver microsomes and cryopreserved human 1.7 h for the 100 and 200 μg LSD doses, respectively. Subjective
hepatocytes with LSD. They positively identified 2-oxo-3-OH- peak effects were reached 2.8 and 2.5 h after administration of
LSD in all human liver microsomal and human hepatocyte LSD 100 and 200 μg, respectively. There was a close relationship
fractions incubated with LSD. In a later in vitro study that used between the plasma LSD concentration and subjective response
human liver microsomes, LAE was determined to be the major within subjects. Half-maximal effective concentration values were
metabolite.61 Faed and McLeod62 reported the elimination in the range of 1 ng/mL. Oral LSD presented dose-proportional
half-life for LSD in man as 3.6 h. LSD and its metabolites were pharmacokinetics and first-order elimination up to 12 h. The
reported to be detectable in the urine for as long as 4 days after effects of LSD were related to changes in plasma concentrations
ingestion. over time, with no evidence of acute tolerance.
Canezin et al.63 found the following LSD metabolites in
human urine: nor-LSD, LAE, 2-oxo-LSD, 2-oxy-3-hydroxy-LSD,
13- and 14-hydroxy-LSD as glucuronides, lysergic acid ethyl-2-
■ PHARMACOLOGY, MEDICINAL CHEMISTRY, AND
STRUCTURE−ACTIVITY RELATIONSHIPS
hydroxyethylamide (LEO), and “trioxylated LSD.” The major Passie has presented a comprehensive review on the pharmacol-
metabolite in urine is 2-oxy-3-OH-LSD, which could not be ogy of LSD,67 and the present author also has provided a recent
detected in blood plasma. review that includes aspects of the pharmacology of LSD.68
In order to characterize and quantify better the human metab- Although LSD has high affinity for a variety of G protein coupled
olites of LSD, Dolder et al.64 recently developed and validated a receptors,67 the potent psychoactive effects of LSD can be
liquid chromatography triple quadrupole tandem mass spec- attributed to its partial agonist activity at the brain serotonin
trometry (LC-MS/MS) method for the quantification of LSD, 5-HT2A receptor.68 In behavioral studies in rats, however, there is
iso-LSD, 2-oxo-3-OH-LSD, and nor-LSD in plasma samples a time-dependent change in pharmacology, from initial 5-HT2A
from 24 healthy subjects after administration of 100 μg (free base) receptor activation to dopamine D2-like pharmacology at later
LSD in a clinical trial. In addition, recently described in vitro metab- times.69−72
olites, including LAE, lysergic acid LEO, 2-oxo-LSD, trioxylated- Although early research from numerous in vitro and animal
LSD, and 13- and 14-hydroxy-LSD, could be identified. A reversed behavioral models had clearly shown the key importance of the
phase chromatography column after turbulent-flow online 5-HT2A receptor,68,73 validation in human clinical studies was
extraction was used to separate LSD and its metabolites. A triple provided by research from the Vollenweider laboratory, in Zürich,
quadrupole LC-MS/MS instrument was employed for identi- Switzerland. It was first shown in 1998 that ketanserin, a selective
fication and quantification of metabolites. The limit of quanti- 5-HT2A antagonist, could block the psychedelic effects of psilo-
fication was 0.05 ng/mL for LSD, iso-LSD, and nor-LSD, and cybin, a naturally occurring tryptamine with psychoactive effects
0.1 ng/mL for 2-oxo-3-OH-LSD. The limit of detection was similar to LSD.74 In the past year, however, several clinical studies
0.01 ng/mL for all compounds. The method was described as have appeared from the same laboratory demonstrating that the
accurate, precise, and the calibration range within the range of psychoactive properties of LSD also can be blocked by pretreat-
expected plasma concentrations. LSD was quantified in the ment with ketanserin.23,24,29,30
plasma samples of the 24 subjects of the clinical trial. Iso-LSD, The structure−activity relationships of lysergic acid amides are
2-oxo-3-OH-LSD, nor-LSD, LAE, LEO, 13/14-hydroxy-LSD, unique, in that virtually any structural change leads to marked
and 2-oxo-LSD could be detected only sporadically, and concen- attenuation in potency and altered qualitative human psycho-
trations were too low for quantification. pharmacology.75 No other amide that has been studied, other
Dolder et al.65 characterized the pharmacokinetic profile, than the N,N-diethyl, appears to have potency or psychophar-
pharmacokinetic-pharmacodynamic relationship, and urine macology comparable to that of LSD, although some other
recovery of LSD and its main metabolite after administration amides do have in vitro or uterotonic activities similar to LSD.76
of a single oral dose of lysergic acid diethylamide (200 μg of free The one exception may be a rigid analogue of LSD, where the
base) in 8 male and 8 female healthy subjects. Only 1% of the two diethyl groups of the diethylamide moiety are tethered into a
orally administered LSD was eliminated in urine as unchanged 2,4-dimethylazetidine ring with the 2S,4S stereochemistry in the
drug, with 13% eliminated as 2-oxo-3-OH-lysergic acid azetidine moiety (Figure 2).52 In general, however, there is a
diethylamide within 24 h. No sex differences were observed in paucity of human data for other LSD congeners. N(1)-acetyl or
the pharmacokinetic profiles of lysergic acid diethylamide. The -propionyl derivatives of LSD appear to be prodrugs, and are
acute subjective and sympathomimetic responses to lysergic acid converted into LSD in the body.77 Some of these have been sold
diethylamide lasted up to 12 h and were closely associated with on the “recreational chemicals” market, and their psychophar-
the concentrations in plasma over time. macology is given in anecdotal reports https://erowid.org/
Dolder et al.66 analyzed pharmacokinetic data from two pub- experiences/subs/exp_1PLSD.shtml.
lished placebo-controlled, double-blind, crossover studies using One analogue of LSD modified in the amide moiety has been
orally administered LSD 100 and 200 μg (free base) in 24 and reported to have human activity approximately equipotent
16 subjects, respectively. The pharmacokinetics of the 100 μg to LSD. The lysergamide of 2S,4S-dimethylazetidine52 has been
dose was presented for the first time, and data for an earlier study sold as “LSZ” and anecdotal reports of its human activity
of a 200 μg dose65 were reanalyzed. Plasma concentrations of have appeared. Interestingly, the crystal structure of LSD bound
LSD, subjective effects, and vital signs were assessed repeatedly. within the human serotonin 5-HT2B receptor was recently
Concentration-effect relationships were described using phar- reported.78 The conformation of the LSD molecule within the
macokinetic-pharmacodynamic modeling. Geometric mean crystal structure was essentially superimposable on the structure
(95% confidence interval) maximum plasma concentration of the lysergamide of 2S,4S-dimethylazetidine.52
values of 1.3 (1.2−1.9) and 3.1 (2.6−4.0) ng/mL were reached The only other LSD analogues reported to have significant
1.4 and 1.5 h after administration of 100 and 200 μg of LSD, respec- human activity are N(6)-ethyl-norLSD (“ethlad”)79−81 and
tively. The plasma half-life was determined as 2.6 h (2.2−3.4 h). N(6)-allyl norLSD (“Al-lad”).79,81,82
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Figure 2. LSD analogues reported to have significant human activity.

ADVERSE EFFECTS AND DOSAGE

Comprehensive reviews of clinical outcomes of experimental
LSD studies conducted in the United States and the United
Kingdom during the 1950s and 1960s identified very low rates of
adverse effects.83−85 Although United States Food and Drug
Administration approved clinical studies of LSD ended with the
passage of the controlled substances act (CSA) of 1970, con-
trolled clinical studies have recently resumed in Europe, although
not as yet in the United States.18,24,25,33,86−89
Although LSD is classified as a Schedule 1 drug with no safe or Figure 3. Comparison of the structure of LSD with that of serotonin.
recognized therapeutic use, its use by the public has continued
over the past 45 years.90,91 Interestingly, reports of psychological especially the mother, were most often blamed for not providing
adverse events outside of formal and approved research settings emotional nourishment to the child, and being “bad parents.”
have declined over the past several decades. That may be due to The connection between the potent psychoactive effects of LSD,
general availability of lower doses, access to better and more accu- its structural relationship to serotonin, and the detection of
rate information about LSD, improved psychological preparation, serotonin in the brain was a sort of “ah ha” moment. One can thus
and greater attention given to supportive environmental conditions. reasonably argue that the discovery of LSD catalyzed the begin-
Experts generally recognize that LSD is an extremely phys- ning of the entire field of serotonin neuroscience, and especially
iologically safe substance, when moderate dosages are used the role of serotonin in brain function. By way of illustration, in
(50−200 μg) in controlled settings, with only modest elevations 1952, there were only 10 publications in the National Library of
of blood pressure, heart rate, and body temperature.26,87,92 LSD Medicine concerning serotonin, nearly all of them dealing with
does not show any dependence liability. It is estimated that some aspect of its action in the periphery, e.g., its ability to
10.2% of the current United States population has ever taken constrict blood vessels. Only 8 years later, in 1960, there were
LSD,93 indicating that approximately 31 million people have ever 300 publications on serotonin, 35 of which involved studies of
used LSD, with not a single documented death due to LSD at serotonin in the brain. Green99 has provided an interesting
recreational doses.93−95 overview of the 1950−1970 period of intense research activity
Although fatalities after LSD use can occur when the intox- following the detection of serotonin in the brain.
ication leads the user to carry out dangerous activities such as walk- As of today, it is clear that the combination of modern brain
ing across a busy highway, attempting to swim, rock climbing, etc., imaging methods with LSD and other psychedelics offers an
there are only two documented cases where LSD presumably extremely powerful approach to understanding brain dynamics.
directly led to fatality. In both cases, post-mortem analysis indi- These approaches are providing insight into the way that
cated that the decedents had ingested massive doses of LSD.96

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different brain regions communicate with each other, and how
those communications affect behavior, perception, and con-
HISTORY AND IMPORTANCE IN NEUROSCIENCE sciousness itself. The name “psychedelic,” which essentially means
Although the high potency and unique psychopharmacology of “mind manifesting” appears today to be an apt description for
LSD are widely recognized, often overlooked is one very this class of psychoactive agents. This knowledge will no doubt
important scientific consequence of the discovery of LSD. inform future approaches to mental health treatments, irrespec-
As noted earlier, the powerful psychological effect of LSD was tive of whether or not psychedelics themselves become useful
accidently discovered in 1943. Only a decade later, in 1953, therapeutic agents.
serotonin was detected in mammalian brain.97 Scientists quickly The final chapter on the importance of LSD to neuroscience
noticed the tryptamine moiety embedded within LSD to be the and medicine is yet to be written. Although the early enthusiasm
same scaffold as in the chemical structure of serotonin (Figure 3). for the therapeutic value of LSD has faded, recent studies,
Thus, only one year later, Woolley and Shaw98 proposed that especially with the related molecule psilocybin, have provided
“mental disturbances caused by lysergic acid diethylamide were positive results in small pilot studies suggesting that psychedelics
to be attributed to an interference with the action of serotonin in may be useful in treating depression, anxiety, and a variety of
the brain.” To put that finding into context, in the 1940s, and addictions.100 The major pharmaceutical companies have
earlier, psychiatry was primarily focused on the use of psycho- reduced or eliminated their research efforts toward development
analytical methods; there was no general recognition that mental of psychiatric drugs. Most psychiatrists bemoan the lack of
disturbances could be attributed to neurochemistry. When a improved drugs for treatment of psychiatric illnesses, with no
child was diagnosed with a mental disorder, the parents, hope on the horizon for new more efficacious medicines anytime
2340 DOI: 10.1021/acschemneuro.8b00043
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soon. It seems possible that LSD, and other psychedelics, may qualitative study of acute and sustained subjective effects. J.
offer a new therapeutic approach,100,101 perhaps fulfilling the Psychopharmacol. 29 (1), 57−68.
promise that they seemed to offer more than half a century ago. (21) Kaelen, M., Barrett, F. S., Roseman, L., Lorenz, R., Family, N.,

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Bolstridge, M., Curran, H. V., Feilding, A., Nutt, D. J., and Carhart-
Harris, R. L. (2015) LSD enhances the emotional response to music.
AUTHOR INFORMATION Psychopharmacology (Berl) 232 (19), 3607−14.
Corresponding Author (22) Kaelen, M., Roseman, L., Kahan, J., Santos-Ribeiro, A., Orban, C.,
*E-mail: [email protected]. Lorenz, R., Barrett, F. S., Bolstridge, M., Williams, T., Williams, L., Wall,
M. B., Feilding, A., Muthukumaraswamy, S., Nutt, D. J., and Carhart-
ORCID Harris, R. (2016) LSD modulates music-induced imagery via changes in
David E. Nichols: 0000-0002-1129-1697 parahippocampal connectivity. Eur. Neuropsychopharmacol. 26 (7),
Notes 1099−109.
(23) Barrett, F. S., Preller, K. H., Herdener, M., Janata, P., and
The author declares no competing financial interest.

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Vollenweider, F. X. (2017) Serotonin 2A Receptor Signaling Underlies
LSD-induced Alteration of the Neural Response to Dynamic Changes in
ACKNOWLEDGMENTS Music. Cereb Cortex, 1−12.
The author gratefully acknowledges translation into English of (24) Preller, K. H., Herdener, M., Pokorny, T., Planzer, A.,
the original German clinical reports by Dr. Daniel Wacker. Kraehenmann, R., Stampfli, P., Liechti, M. E., Seifritz, E., and

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Vollenweider, F. X. (2017) The Fabric of Meaning and Subjective
Effects in LSD-Induced States Depend on Serotonin 2A Receptor
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