Dark Classics in Chemical Neuroscience: Lysergic Acid Diethylamide (LSD)

This literature review (2018) of the history of LSD looks back at the research that has been done after its (somewhat) accidental discovery in 1943 by Albert Hofmann.

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 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 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.”

Authors: David E. Nichols

Summary

Lysergic acid diethylamide (LSD) is a potent psychoactive agent that produces dramatic alterations of consciousness after submilligram (20 g) oral doses. It was found to be physiologically very safe and nonaddictive, and was used in controlled experiments. LSD was widely hailed by psychiatry as a breakthrough drug in the 1950s and early 1960s, but clinical research with LSD ended by about 1970. Within the past 5 years, research with LSD has begun in Europe.

■ INTRODUCTION

LSD was first synthesized in 1938 by Swiss natural products chemist Dr. Albert Hofmann, working in the Sandoz laboratories in Basle, Switzerland. It had a strong contractile effect on the uterus and caused the mice to become restless after administration of the new drug.

Hofmann suspected that his mental disturbance might have been caused by the lysergic acid diethylamide he had been working with, and decided to conduct a self-experiment with the LSD tartrate. He experienced much stronger symptoms than the first time, and his physician was called.

Hofmann recalls1 that the most outstanding symptoms of his crisis were vertigo, visual disturbances, motoric unrest, alternating with paralysis, a dry, constricted sensation in the throat, and a feeling of choking.

This self-experiment showed that LSD-25 behaves as an extraordinarily potent psychoactive substance. Hofmann also says that his “conscious recording function” was not interrupted, even at the peak of the LSD experience.

When Hofmann wrote his report about his extraordinary experience with LSD-25, the director of the pharmacology department, Professor Ernst Rothlin, was incredulous. However, Hofmann’s experiment was repeated with only one-third of the dose, and the effects were still extremely impressive.

Hofmann pondered how this substance could have gotten into his body, and honestly did not know. It is possible that he contacted a solution of the free base during column chromatography, and absorbed it through his skin.

In 1947, a scientific study was published on the effects of LSD. It included 29 normal subjects and 20 treatment-resistant schizophrenics, and included a comprehensive analysis of effects, with very detailed descriptions for five of the normal subjects.

In normal subjects, LSD produced feelings of euphoria, visual patterns, feeling young, beautiful, and reborn, and subjects reported being more sensitive to music. Schizophrenics had less of an effect than normal, and none were made worse by the LSD.

Gion Condrau and Stoll reported that LSD had been administered 240 times to healthy volunteers and 36 patients with psychiatric illness. The patients had subtle psychological effects, and were less resistant to LSD than normals.

LSD was first brought to the United States in 1949 for testing by Boston psychiatrist Max Rinkel and Los Angeles psychiatrist Nick Bercel. LSD was made available to research institutes and physicians as an experimental drug, and two different approaches to psychotherapy with LSD were used: psycholytic and psychedelic.

A second treatment approach, known as psychedelic therapy, used LSD to induce mystic/religious experiences. Patients underwent daily psychotherapy for weeks prior to a single high dose administration of LSD.

Eric Kast compared dihydromorphinone and meperidine with LSD in a double-blind study with 50 gravely ill patients, and found that LSD was inferior in its analgesic action, but gave the patients a peculiar disregard for their situations, which was beneficial to their own psychic states.

LSD was widely hailed as a new breakthrough for psychiatry, but early clinical studies were often inconclusive. However, a recent meta-analysis found that a single dose of LSD had a significant beneficial effect on alcohol misuse at the first reported follow-up assessment.

The passage of the Controlled Substances Act (CSA) of 1970, which classified LSD as having a high potential for abuse, ended clinical research with LSD for nearly four decades.

Liechti18 reviewed all clinical studies that employed LSD in the last 25 years and concluded that LSD induces bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. LSD also increased feelings of closeness to others, openness, trust, and suggestibility.

Resting-state functional magnetic resonance imaging studies have shown that LSD increases connectivity between brain areas and reduces the integrity of functional brain networks.

A double-blind, randomized, active placebo-controlled pilot study of LSD in 12 patients with anxiety associated with life-threatening diseases found that LSD can reduce anxiety when administered in a methodologically rigorous medically supervised psychotherapeutic setting.

A follow up study found that the benefits of STAI were sustained over a 12 month period, and participants reported insightful, cathartic, and interpersonal experiences, accompanied by a reduction in anxiety and an increase in quality of life.

Although only one recent therapeutic trial of LSD has been conducted, the drug is now being used in a variety of clinical research studies to understand how LSD affects emotion or affect. Kaelen et al.21 tested the hypothesis that LSD enhances music-evoked emotions by listening to five different tracks and completing visual analogue scales and the nine-item Geneva Emotional Music Scale. The authors conclude that LSD enhances the emotional response to music.

In a second study, Kaelen et al.22 investigated the interaction between LSD and music-listening on eyes-closed imagery using fMRI. They found that the PHC was more connected to the VC and the PHC to VC information flow was increased in the interaction between music and LSD.

Barrett et al.23 found that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, as well as areas involved in memory, emotion, and self-referential processing.

LSD enhanced suggestibility in 10 healthy volunteers in a within-subject placebo-controlled design, but not in cued mental imagery. This suggests that LSD may have implications for its use as an adjunct to psychotherapy, where suggestibility plays a major role.

Dolder et al.26 investigated the acute effects of LSD on emotional processing and social behavior using the Face Emotion Recognition Task (FERT) and Multi-faceted Empathy Test (MET). They found that LSD enhanced participants’ desire to be with other people and increased their prosocial behavior.

With eyes-closed under psychedelics, the brain may function as if there is visual input when there is none. Roseman et al.27 found that the difference between RSFC of patches with congruent retinotopic representations and those with incongruent representations increased significantly under LSD relative to placebo.

Terhune et al.28 investigated the impact of LSD on color experiences in response to standardized graphemes and sounds. They found that LSD-induced synesthesia-like experiences did not exhibit consistency or inducer-specificity.

LSD produced dreamlike waking imagery that depended on 5-HT2A receptor activation, and was related to subjective drug effects. Ketanserin fully blocked both LSD-induced increases in cognitive bizarreness and changes in state of consciousness.

Kraehenmann et al.30 found that LSD increases primary process thinking, which is related to disembodiment and blissful state on the 5D-ASC. Ketanserin fully blocked both LSD-induced increases in primary process thinking and changes in state of consciousness.

Liechti et al.31 conducted two placebo-controlled, double-blind, crossover studies using oral administration of 100 and 200 g of LSD free base in 24 and 16 subjects, respectively. They found that 200 g of LSD induced mystical experiences that were comparable to those in patients who underwent LSD-assisted psychotherapy.

Recent studies have shown that psychedelics affect brain dynamics and functional connectivity. The increased global connectivity observed with LSD correlated with subjective reports of “ego dissolution”.

Carhart-Harris et al.33 used three complementary neuroimaging techniques to examine the effects of LSD on the visual cortex. They found that increased visual cortex CBF, decreased visual cortex alpha power, and a greatly expanded primary visual cortex functional connectivity profile were all associated with visual hallucinations.

Timmermann et al.34 presented an auditory oddball paradigm to 20 healthy participants under LSD and placebo conditions, and recorded brain activity using MEG. They found that backward connectivity was modulated in the LSD condition.

Schmidt et al.35 found that 5-HT2A receptor activation by LSD leads to a breakdown of inhibitory processing in the hippocampal-prefrontal cortex, which might subsequently promote the formation of LSD-induced visual hallucinations.

The thalamocortical system is an important site of action for hallucinogenic drugs and an essential component of the neural correlates of consciousness. LSD increases thalamic functional connectivity to various cortical regions and correlates significantly with subjective ratings on auditory and visual drug effects.

Mueller et al.37 used functional magnetic resonance imaging to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. They found that acute administration of LSD reduced engagement of brain regions that mediate emotional processing.

Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Ketanserin, a 5-HT2A-selective receptor antagonist, blocked the effects of LSD on personal relevance processing in humans.

Using fMRI, Lebedev et al.38 showed that increases in brain entropy during LSD use predicted enduring increases in the personality trait openness. The increases in brain entropy were greatest during music listening scans and when “ego-dissolution” was reported during the acute experience.

Recent studies have begun to elucidate the effects of LSD on the human brain, but the underlying dynamics certainly are not yet completely understood. The increased sensitivity to both internal intrinsic activity and external stimuli is a natural functional consequence of tuning brain dynamics toward criticality.

Psychedelics are essentially substances that expand consciousness. They are probably best named “mind manifesting substances”.

The free base of LSD has a melting point of 83 °C and a pKa of 7.8. It forms a crystalline salt with one molecule of D-tartaric acid.

Stoll and Hofmann reported the first synthesis of lysergic acid N,N-diethylamide in 1943,40. This synthesis involved heating ergotamine with anhydrous hydrazine to produce racemic isolysergic acid hydrazide, which was then chemically resolved using d-orl-di(p-toluyl)-tartaric acids.

Hofmann and his Sandoz co-workers prepared (+)-(5R)-isolysergic acid hydrazides in 1966 by adding a strong acid to ergot alkaloid, followed by heating with anhydrous hydrazine.

Several methods were developed to make LSD, including activation of the carboxylic acid function of lysergic acid with carbonyl diimidazole, followed by treatment with diethylamine. One of the simplest syntheses was reported by Johnson et al., which was applicable to preparation of a variety of lysergamides using lysergic acid hydrate.

A recent synthesis employs PyBOP, a crystalline and stable peptide condensing agent, to couple lysergic acid with amines. This synthesis proceeds very rapidly with no epimerization at C8.

LSD is rapidly absorbed from the gut after oral administration and is almost completely metabolized, primarily by the liver. In animals, LSD undergoes several pathways of metabolism, with negligible amounts of unchanged drug found in feces or urine.

[14C]-LSD is almost completely metabolized by rats, guinea pigs, and rhesus monkeys, with only very little of the unchanged drug excreted. Rats and guinea pigs excrete glucuronic acid conjugates of 13- and 14-hydroxy-LSD, as well as 2-oxo-LSD, LAE, and nor-LSD.

In rhesus monkeys, LSD was metabolized into at least nine metabolites, four of which were identified as 13- and 14-hydroxy-LSD, LAE, and a naphthostyril derivative. In humans, 2-oxo-3-OH-LSD was the major metabolite, and the elimination half-life was 3.6 h.

Dolder et al.64 developed and validated a liquid chromatography triple quadrupole tandem mass spectrometry method for the quantification of LSD, iso-LSD, 2-oxo-3-OH-LSD, and nor-LSD in plasma samples from 24 healthy subjects after administration of 100 g (free base) LSD in a clinical trial.

Dolder et al.65 observed that lysergic acid diethylamide has a similar pharmacokinetic profile in males and females, with the acute subjective and sympathomimetic responses lasting up to 12 h.

Dolder et al.66 analyzed pharmacokinetic data from two placebo-controlled, double-blind, crossover studies using orally administered LSD 100 and 200 g in 24 and 16 subjects, respectively.

LSD’s potent psychoactive effects can be attributed to its partial agonist activity at the brain serotonin 5-HT2A receptor. LSD’s pharmacology changes over time, from initial 5-HT2A receptor activation to dopamine D2-like pharmacology at later times.

Early research had shown that the 5-HT2A receptor was important for the psychoactive effects of psilocybin and LSD. In the past year, several clinical studies have shown that LSD can also be blocked by ketanserin.

Lysergic acid amides are unique in that virtually any structural change leads to marked attenuation in potency and altered qualitative human psychopharmacology. Some amides have in vitro or uterotonic activities similar to LSD, but there is a paucity of human data for other LSD congeners.

A lysergamide analogue of LSD has been reported to have human activity approximately equipotent to LSD. The crystal structure of LSD bound within the human serotonin 5-HT2B receptor was recently reported.

Comprehensive reviews of clinical outcomes of experimental LSD studies conducted in the United States and the United Kingdom identified very low rates of adverse effects.

Although LSD is classified as a Schedule 1 drug, its use by the public has continued over the past 45 years. Experts generally recognize that LSD is an extremely physiologically safe substance, with only modest elevations of blood pressure, heart rate, and body temperature.

Although fatalities can occur after LSD use, there are only two documented cases where LSD presumably directly led to fatality. LSD was accidentally discovered in 1943. Ten years later, serotonin was detected in mammalian brain, and scientists immediately noticed the tryptamine moiety embedded within LSD to be the same scaffold as in the chemical structure of serotonin. In the 1940s and earlier, psychiatry was focused on psychoanalytical methods, and there was no general recognition that mental disturbances could be attributed to neurochemistry. The discovery of LSD catalyzed the beginning of the entire field of serotonin neuroscience, and especially the role of serotonin in brain function.

Modern brain imaging methods combined with LSD and other psychedelics offer a powerful approach to understanding brain dynamics. This knowledge will no doubt inform future approaches to mental health treatments.

LSD and other psychedelics may offer a new therapeutic approach to treating depression, anxiety, and a variety of addictions, although major pharmaceutical companies have reduced or eliminated their research efforts toward development of psychiatric drugs.