Key insights on history, identification and naming, synthesis, and emerging analogs

Camille Watson-Gooden and Danielle St. Germaine, experts in lysergamide chemistry and analysis at Cayman Chemical, discuss the history, modifications, fragmentation, and new emerging analogs of lysergamides.

Lysergamide History (50s)

Lysergamides are a class of alkaloids with a tetracyclic ergoline core structure. The ergoline scaffold allows for variable targeting of serotonin, dopamine, and adrenergic receptors. Many current and historical pharmaceuticals utilize the ergoline scaffold to target the receptors for these endogenous ligands with ergoline derivatives. Pharmaceutical preparations inspired by ergot alkaloids have been used to prevent and/or treat several conditions, ranging from postpartum hemorrhage and migraine headaches to Parkinson’s disease and vascular dementia.

LSD (lyserg-säure-diäthylamid A.K.A. lysergic acid diethylamide, LAD) (Figure 1) is the most notorious lysergamide. LSD was first synthesized in 1938 by Dr. Albert Hofmann, a chemist at the Sandoz AG Pharmaceutical Company in Switzerland.

Figure 1. Structure of LSD.

Research Tools for LSD

Lysergamide Pharmacology (10m 32s)

The psychedelic experience of LSD is linked to activation of serotonin (5-HT) receptors, in particular, the 5-HT_2A receptor subtype, though other mechanisms may also be at play. LSD has mixed agonist properties at 5-HT, dopamine D₂, and α_1A- and α_1B-adrenergic receptors.

Several chemical modifications to the ergoline structure can influence the psychedelic effects of lysergamides. The two conventions used for numbering lysergamides are the Hofmann and IUPAC systems. The Hofmann notation is most common.

The psychedelic properties of LSD depend on the stereochemistry of positions 8 and 5, the saturation at position 9, and the chain length of substituents on the amide position (Figure 2). Substitution at the 2 position is inactivating. Clinical trials exploring the use of 2-bromo LSD are set to begin in 2024. These critical sites responsible for the psychedelic properties of LSD are demarcated on the figure below with asterisks.

Figure 2. Modifications that alter the psychedelic properties of LSD. 

Lysergamide Identification and Naming (16m 34s)

Variations to the tetracyclic ergoline core typically occur at three main regions (Figure 3). These modifications give rise to LSD analogs.

The main modifications are:

1. Amide N¹⁸ substitutions

2. Ring (D) substitutions at the N⁶ position

3. Ring (B) substitutions

The naming conventions used for LSD analogs typically denote the identity of the substituents in the analog. Some consideration when naming is also given based on choosing unique names that distinguish them from other lysergamides as well as auditory and visual appeal of the chosen name.

Figure 3. Location of lysergamide modifications.

Naming Systems for Lysergamides

View the Standardized Naming System for Substituted Tryptamines Article

Amide N¹⁸ Substitutions

The nomenclature of the amide portion of lysergamides sometimes derives from the ethylamino substituents in tryptamine nomenclature. These substitutions also generally follow the tryptamine nomenclature for naming, where the smallest molecule is named first, followed by the larger substituents.

Amide N¹⁸ Substitutions

* The tryptamine naming convention does not apply for lysergamides with single amide N¹⁸ substitutions.

Ring (D) Substitutions at N⁶ Position

Lysergamides with these substitutions follow a Shulgin-style naming convention using LAD as the parent name.

Ring (D) Substitutions

Ring (B) Substitutions

Lysergamides with these substitutions follow the Hofmann-style naming convention using LSD as the parent name. The use of "1" in the lysergamide name denotes the position at the indole nitrogen, and the next letter in the abbreviated name indicates the identity of the substituent.

Ring (B) Substitutions

Lysergamide Synthesis & Starting Materials (23m 30s)

Understanding the synthesis of lysergamides is critical to understanding what new compounds may appear on user sites, forums, and in forensic casework. Clandestine chemists prefer to use inexpensive starting materials in lysergamide synthesis.

Amide N¹⁸ Substitutions

The diethylamide group of LSD can easily be swapped out using base hydrolysis to cleave the lattice to form lysergic acid, followed by amino acid coupling or an acid chloride strategy to aminate the LSD analog (Figure 4).

Figure 4. Amide N¹⁸ substitution chemistry.

Piperidine N⁶ Substitutions

The N⁶ position of the piperidinyl ring may be demethylated to form nor-LSD (nor-without) and then re-alkylated with an alkyl chain containing an appropriate leaving group to form the appropriate analog (Figure 5).

Figure 5. Piperidine N⁶ substitution chemistry.

Indole Ring B Substitutions

Adding acyl or alkyl substituents to the N¹ nitrogen is the simplest way for clandestine chemists to skirt regulatory measures. In recent years, an increase in indole ring B-substituted lysergamides have appeared on illicit markets. Clandestine chemists favor acyl substituents, which are derived from commercially available carboxylic acid starting materials (Figure 6).

Figure 6. Indole ring B substitution chemistry.

Byproducts of Lysergamide Synthesis

Lysergamides are notoriously unstable and degrade in the presence of light. When subjected to strong acidic and basic conditions, the amide of LSD is epimerized to its diastereomer iso-LSD. These compounds have the same fragments but slightly different retention times.

EI-MS Fragmentation of Lysergamides (29m 05s)

The EI-MS fragmentation pattern of these substances can be used to aid in the identification of lysergamides. We have collected five tips to consider for EI-MS interpretation of lysergamide fragmentation patterns.

Five Tips for EI-MS Interpretation

1. Lysergamides typically show the MW ion peak

2. A peak (a base peak in some cases) at m/z = 221 is an indicator that the substituent at N⁶ is a methyl group

3. Analogs with an additional substituent at N¹ (typically an acyl group) often show a second base peak with m/z = [221 + mass of acyl group] -1

4. Analogs with different substituents at the N6 position often show m/z = 207 as a base peak. The peak at m/z = 221 is absent

5. Observation of the m/z = 72 peak (Figure 7) indicates that N¹⁸ has one of the following substituents*:

1. LSD
   

2. MiPLA
   

3. LAMPA
   

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