Lysergic Acid Diethylamide (LSD): An In-Depth Exploration

General Information

Lysergic Acid Diethylamide (LSD), colloquially known as acid, is a powerful psychoactive substance renowned for its ability to induce profound alterations in perception, mood, and consciousness. Chemically classified as a psychedelic compound, LSD belongs to the ergoline family and is derived from lysergic acid, a naturally occurring compound found in the ergot fungus that grows on certain grains, notably rye. The synthesis of LSD was first accomplished by Swiss chemist Albert Hofmann in 1938 as part of research into ergot alkaloids. However, its psychoactive properties were not discovered until April 19, 1943, when Hofmann accidentally touched a small amount and experienced its mind-altering effects.

LSD formula and LSD solution

LSD gained prominence in the 1950s and 1960s as a key component of countercultural movements, particularly within the realms of art, music, and spirituality. Its association with figures such as Timothy Leary and the exploration of consciousness led to widespread interest in its potential as a tool for self-discovery and transcendence. However, due to concerns about its safety and potential for abuse, LSD was classified as a Schedule I controlled substance in the United States in 1970, effectively halting most research into its therapeutic applications.

Despite its illegality, LSD remains a popular recreational drug, with users seeking its hallucinogenic effects, which can include visual and auditory distortions, synesthesia, and profound alterations in thought patterns and ego perception. LSD is typically ingested orally, most commonly in the form of blotter paper impregnated with the compound or as liquid drops absorbed onto various substrates. The effects of LSD are dose-dependent, with lower doses producing milder alterations in perception and higher doses leading to more intense psychedelic experiences. The duration of effects typically ranges from 6 to 12 hours, with residual effects potentially lasting up to 24 hours or more.

LSD marks

While LSD is often associated with recreational use, there is ongoing interest in its potential therapeutic applications. Research conducted in the mid-20th century suggested that LSD could be beneficial in the treatment of various psychiatric disorders, including depression, anxiety, and addiction. Recent studies have also explored its potential in end-of-life care, particularly for patients facing terminal illness. However, legal and regulatory barriers have hindered progress in this area, limiting the availability of LSD for clinical research and therapeutic use.

Physical Properties

Lysergic Acid Diethylamide (LSD) possesses several distinctive physical properties that contribute to its unique characteristics and methods of use.

Appearance: Pure LSD typically presents as a colorless, odorless crystalline solid. However, due to its extreme potency, LSD is often produced and distributed in the form of a salt to facilitate handling and dosing. Common salt forms include LSD tartrate or LSD hydrochloride, which are more stable and soluble than the pure compound.

Solubility: LSD exhibits limited solubility in water but is highly soluble in organic solvents such as ethanol and dimethyl sulfoxide (DMSO). This solubility profile influences the methods used for its synthesis, purification, and formulation into various dosage forms. For recreational use, LSD is commonly dissolved in a solvent and applied to a carrier substrate, such as blotter paper or gelatin squares, for oral ingestion.

Water 67.02 mg/mL (20 °C) [free base]

Melting Point:

• LSD Base 80-85°C
• LSD tartrate 198-200°C

LSD crystalls

Chemical Properties

Lysergic Acid Diethylamide (LSD) is characterized by a complex array of chemical properties that underlie its psychoactive effects and pharmacological activity.

The chemical structure of LSD consists of a bicyclic ring system with a diethyl moiety attached to the nitrogen atom. This unique structure endows LSD with high potency and selectivity for specific receptor targets in the brain.

LSD Isomers

Stereochemistry: LSD is a chiral compound with two stereocenters at the carbon atoms C-5 and C-8, so that theoretically four different optical isomers of LSD could exist. LSD, also called (+)-d-LSD, has the absolute configuration (5R,8R). 5S stereoisomers of lysergamides do not exist in nature and are not formed during the synthesis from d-lysergic acid. Retrosynthetically, the C-5 stereocenter could be analysed as having the same configuration of the alpha carbon of the naturally occurring amino acid L-tryptophan, the precursor to all biosynthetic ergoline compounds.

However, LSD and iso-LSD, the two C-8 isomers, rapidly interconvert in the presence of bases, as the alpha proton is acidic and can be deprotonated and reprotonated. Non-psychoactive iso-LSD which has formed during the synthesis can be separated by chromatography and can be isomerized to LSD.

Pure salts of LSD are triboluminescent, emitting small flashes of white light when shaken in the dark. LSD is strongly fluorescent and will glow bluish-white under UV light. The stereochemistry of LSD is thought to play a significant role in its pharmacological effects and interactions with serotonin receptors in the brain.

Acid-Base Properties: LSD is a weakly basic compound that can undergo protonation or deprotonation depending on the pH of its environment. In its neutral form, LSD exists predominantly as the freebase, which is less soluble in water and less bioavailable compared to its salt forms. In acidic conditions, such as in the stomach after oral ingestion, LSD becomes protonated and converts to its water-soluble salt forms, such as LSD tartrate or LSD hydrochloride, which enhances its absorption and bioavailability.

• IUPAC Name: (6aR,9R)-N,N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide
• CAS Number: 50-37-3
• Other names: D-lysergic acid diethylamide; N, N-diethyl-D-lysergamid; Lysergsäure diethylamid; LAD; LSD; LSD-25; 9,10-Didehydro-N,N diethyl-6-methylergoline-8-β-carboxamide

Reagent Qualitative Tests

Exposing compounds to the reagents gives a colour change which is indicative of the compound under test.

Synthesis Ways

LSD is an ergoline derivative. It is commonly synthesized by reacting diethylamine with an activated form of lysergic acid. Activating reagents include phosphoryl chloride and peptide coupling reagents like PyBOP.

LSD from LSA with phosphoryl chloride

LSD from LSA with PyBOP

Lysergic acid is made by alkaline hydrolysis of lysergamides like ergotamine, a substance usually derived from the ergot fungus on agar plate; or, theoretically possible, but impractical and uncommon, from ergine (lysergic acid amide, LSA) extracted from morning glory seeds. Lysergic acid can also be produced synthetically, although these processes are not used in clandestine manufacture due to their low yields and high complexity.

Effects and Dosage

LSD is most commonly consumed orally, either by ingesting blotter paper impregnated with the compound or by taking liquid drops placed directly on the tongue. Blotter paper, often adorned with colorful designs or patterns, is a popular medium for distributing LSD due to its ease of handling and dosing. Liquid LSD, usually dissolved in ethanol or another solvent, offers greater flexibility in dosage and administration but requires careful measurement to avoid overdosing.

LSD sugar cube

Subjective effects encompass alterations in visual patterns, hallucinatory perceptions, distortion of time perception, heightened self-reflection, abstract thinking, amplified enjoyment of music, feelings of intense happiness, and a diminished sense of self. The use of LSD is commonly associated with experiences that are described as mystical, sometimes believed to aid in introspection and personal development. It has been hailed as the inaugural contemporary entheogenic substance, a category typically reserved for traditional botanical preparations or concentrates.

In contrast to many illicit substances, LSD has not been definitively linked to physiological toxicity or addictive properties. Nevertheless, adverse psychological responses such as extreme anxiety, feelings of persecution, false beliefs, and episodes of psychosis can occur, especially in individuals predisposed to mental health conditions.

Pharmacology

According to various studies, LSD acts as a partial agonist at most serotonin receptor subtypes, including the 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C and 5-HT6 receptors, with high affinities. The 5-HT3 and 5-HT4 receptors are excluded. 5-HT5B receptors, which have not been found in humans, also have a high affinity for LSD.

The mechanism of LSD's psychedelic effects is thought to be agonist (binding) activity at the 5-HT2A, 5-HT2C, and 5-HT1A receptor subtypes, with high affinities. Further information about how altered serotonin signaling may lead to LSD's signature cascade of visual and cognitive effects is available here. It should be noted that the mechanism is not fully understood.

Binding affinities of LSD for various receptors.

Recent research has also found that LSD activates different intracellular signaling cascades than endogenous serotonin even when bound to the same receptor sites. Because intracellular signaling cascades influence gene expression, LSD-induced signaling events within cells may inappropriately alter gene expression, which in turn may lead to changes in neuronal state and subsequently cognition.

These findings help explain why the behavioral effects can resemble paranoid schizophrenia in humans.

The study concludes that acute LSD usage increases expression of a small set of genes in the mammalian brain that are involved in a wide array of cellular functions implicated in synaptic plasticity, glutamatergic signaling, cytoskeletal architecture and perhaps communication between the synapse and nucleus.

Additionally, studies have shown that LSD possesses binding efficacy at all dopamine and all norepinephrine receptors. Most serotonergic psychedelics are not significantly dopaminergic, so LSD is unique in this respect. In particular, LSD's agonist activity at the D2 receptor has been shown to contribute to its subjective effects.

Storage

LSD is relatively unstable in the presence of light, heat, and oxygen, which can degrade the compound over time. To maintain its potency and integrity, LSD should be stored in a cool, dark, and dry environment, preferably in airtight containers. Proper storage conditions are essential for preserving the quality of LSD-containing products and minimizing degradation during handling and transportation.

Conclusion

In conclusion, Lysergic Acid Diethylamide (LSD) remains a substance of profound interest and controversy, its rich history and complex pharmacological effects rendering it a subject of perpetual fascination. Despite its classification as a Schedule I controlled substance and the legal barriers that impede research, LSD continues to captivate researchers, clinicians, and enthusiasts alike. Its potential therapeutic applications, particularly in the realm of mental health treatment, warrant further investigation under controlled settings. Moreover, LSD's unique ability to alter consciousness and induce mystical experiences underscores its significance as a tool for realizing the human mind and exploring the nature of consciousness itself. However, ethical considerations and safety concerns must guide future research endeavors to ensure responsible exploration of LSD's potential benefits and risks. By navigating these challenges with scientific rigor and compassion, we may unlock new insights into the workings of the brain and pave the way for innovative approaches to healing and self-discovery.

Bibliography

• Bailey, Keith, Denise Verner, and Donald Legault. "Distinction of Some Dialkyl Amides of Lysergic and iso-Lysergic Acids from LSD." Journal of the Association of Official Analytical Chemists 56.1 (1973): 88-99. https://academic.oup.com/jaoac/article-abstract/56/1/88/5711736
• Clark, C. C. "The differentiation of lysergic acid diethylamide (LSD) from N-methyl-N-propyl and N-butyl amides of lysergic acid." Journal of Forensic Sciences 34.3 (1989): 532-546. https://asmedigitalcollection.asme.org/forensicsciences/article/34/3/532/1182282
• Harris, Howard A., and Thomas Kane. "A method for identification of Lysergic acid diethylamide (LSD) using a microscope sampling device with Fourier Transform Infrared (FT/IR) spectroscopy." Journal of Forensic Sciences 36.4 (1991): 1186-1191. https://asmedigitalcollection.asme.org/forensicsciences/article/36/4/1186/1182776
• https://psychonautwiki.org/wiki/LSD
• https://en.wikipedia.org/wiki/LSD