Lysergamides are a class of chemical compounds based on the ergoline scaffold that act on the serotonin 5-HT2A receptor -- they form the chemical family to which LSD-25 and all modern derivatives such as 1BP-LSD and 1Fe-LSD belong. Understanding lysergamides means understanding the foundation of all LSD research.

You do not need to be a chemist to follow this article. I will explain complex relationships in an accessible way -- without sacrificing scientific accuracy. Think of it as a guided tour through the family tree of a fascinating substance class.

Lysergamides (also lysergic acid amides) are a subgroup of ergolines -- a larger class of alkaloids based on a tetracyclic ring system. The name "lysergamide" derives from lysergic acid, the central building block of all compounds in this class.

In chemical terms: a lysergamide is any compound consisting of the lysergic acid scaffold that carries an amide bond at the carboxyl group (position 8). That sounds abstract -- so let's make it visual.

Lysergamides are like a large family. Lysergic acid is the grandmother -- the shared genetic heritage that all family members carry. Each family member (each specific lysergamide) has that heritage but also its own traits: LSD-25 carries a diethylamide group, 1BP-LSD an additional butyryl-propionyl group, 1Fe-LSD a ferrocenyl unit containing an iron atom. All related, yet each member has its own character.

Over 50 different lysergamides are known worldwide -- natural and synthetic. Of these, roughly 15-20 are pharmacologically interesting, and a handful are relevant to our research community.

At the heart of all lysergamides lies the ergoline scaffold -- a system of four interconnected rings (indole ring, cyclohexane ring, and two additional rings). This structure was first described by Jacobs and Craig in 1934 and has been the subject of intensive research ever since.

Why is this scaffold so special? Because its three-dimensional shape bears a striking resemblance to the neurotransmitter serotonin (5-hydroxytryptamine). Both molecules share the indole ring -- and it is precisely this ring component that docks onto the serotonin 5-HT2A receptor in the brain. According to an analysis by Nichols (2004), the affinity of LSD-25 for the 5-HT2A receptor is roughly 500-fold greater than that of serotonin itself -- a remarkable figure that explains why even microgram quantities are effective.

The ergoline scaffold occurs in nature not only in psychoactive compounds. It also forms the basis for several approved medicines:

• Ergotamine: For the treatment of migraine (since the 1920s)
• Bromocriptine: For the treatment of Parkinson's disease and hyperprolactinaemia
• Cabergoline: For the treatment of prolactinomas
• Methysergide: For migraine prophylaxis

This medicinal diversity demonstrates that the ergoline scaffold is no exotic curiosity but a pharmacologically highly relevant blueprint that has been used in mainstream medicine for decades.

Lysergamides are not purely laboratory products -- they have existed in nature for millions of years. Three sources are particularly noteworthy:

Ergot is a parasitic fungus that primarily infects rye and other cereals. It forms dark, elongated sclerotia (dormant structures) on the grain stalk, which contain a variety of ergot alkaloids -- including lysergic acid and related lysergamides.

The history of ergot is also a history of human suffering. In the Middle Ages, the unwitting ingestion of contaminated grain caused so-called "St Anthony's Fire" (ergotism) -- a disease with symptoms ranging from convulsions to gangrene. Historians estimate that between the 9th and 17th centuries, hundreds of thousands of people in Europe fell ill from ergotism. It was Albert Hofmann at Sandoz who systematically investigated ergot alkaloids in 1938, and in doing so -- as the 25th compound in a series -- synthesised LSD-25.

The seeds of the morning glory -- particularly Ipomoea tricolor and Ipomoea violacea -- contain ergine (LSA, lysergic acid amide), a naturally occurring lysergamide. LSA is structurally closely related to LSD-25 but considerably less potent and has a different effects profile.

The Mazatec people in the Mexican state of Oaxaca used morning glory seeds (known as "tlitlitzen" or "ololiuqui") in ritual contexts long before the Spanish colonisation. Ethnobotanist Richard Evans Schultes documented this practice scientifically for the first time in the 1930s. Albert Hofmann identified LSA as the psychoactive compound in 1960 -- and was surprised to find a lysergamide in a plant, since the substance class had until then been known only from fungi.

The LSA content in morning glory seeds is approximately 0.01-0.05% of dry weight -- hundreds of times less concentrated than synthetic lysergamides.

The seeds of the Hawaiian baby woodrose also contain LSA and related ergot alkaloids, at considerably higher concentrations than morning glory -- roughly 0.1-0.5% of seed weight. Argyreia nervosa originates from the Indian subcontinent and was used in Ayurvedic medicine under the name "Vidhara." The psychoactive use of the seeds became known in the Western world only in the 1960s.

Approximately 4-8 seeds contain enough LSA for a noticeable effect -- though many researchers report significantly more pronounced nausea compared with synthetic lysergamides, which is attributed to other alkaloids present in the seeds.

➔ The history of LSD -- from Hofmann to today

Synthetic chemistry has considerably expanded the lysergamide family. Starting from the lysergic acid scaffold, variation of substituents at different positions on the molecule yields new compounds -- each with its own pharmacological profile.

Lysergic acid diethylamide, better known as LSD-25, was synthesised by Albert Hofmann in 1938 and discovered in its psychoactive capacity through the famous "Bicycle Day" (19 April) in 1943. It is the most potent known lysergamide: as little as 25-50 micrograms produce noticeable effects, and 100-200 micrograms lead to a complete alteration of perception.

LSD-25 binds with extraordinary affinity to the 5-HT2A receptor. X-ray crystallography studies (Wacker et al., 2017, Cell) showed that LSD is literally "trapped" within the receptor -- the receptor folds a lid over the LSD molecule, which explains the unusually long duration of 8-12 hours. This study represented a breakthrough in understanding lysergamide pharmacology.

➔ What are LSD derivatives?

From LSD-25, numerous derivatives have been developed. The most important for our research community:

Historical derivatives (research substances):

• ALD-52 (1-Acetyl-LSD): Synthesised as early as the 1950s and explored in psychedelic therapy. Regarded as one of the first "prodrugs" of LSD, although the term was not yet in common use at the time
• ETH-LAD (6-Ethyl-6-nor-LSD): Enhanced visual effects, shorter duration. Investigated by Alexander Shulgin in the 1980s and described in "TiHKAL"
• AL-LAD (6-Allyl-6-nor-LSD): Also documented by Shulgin, known for a gentle effects profile. Duration approximately 6-8 hours -- shorter than LSD-25

Modern prodrug derivatives:

• 1P-LSD (1-Propionyl-LSD): Available from 2015, the first widely distributed prodrug. Propionyl group at N1
• 1cP-LSD (1-Cyclopropionyl-LSD): From 2019, cyclopropionyl group at N1
• 1V-LSD (1-Valeroyl-LSD): From 2021, valeroyl group at N1 -- at that time the largest side chain
• 1Fe-LSD (1-Ferrocenyl-LSD): From 2023, the first to contain a metal atom (iron as a ferrocene unit)
• 1BP-LSD (1-Butyryl-Propionyl-LSD): From 2025, butyryl-propionyl group at N1

The evolution follows a pattern: each new derivative carries a larger or more complex group at the N1 position. There are two reasons -- one pharmacological (different metabolisation rates) and one legal (new structures do not fall under existing bans).

➔ The prodrug principle in detail

Despite their diversity, all lysergamides share certain core characteristics:

All psychoactive lysergamides bind to the serotonin 5-HT2A receptor -- the primary mediator of their effects. This receptor is found mainly in the cerebral cortex, particularly in the prefrontal cortex and the visual cortex. Activation of this receptor influences perception, cognition, and emotional processing.

Interestingly, LSD-25 acts not only at 5-HT2A but at over 40 different receptors -- including 5-HT1A, 5-HT2B, 5-HT2C, dopamine D1 and D2, and various adrenoceptors. This "dirty pharmacology" (Roth et al., 2002) likely contributes to the complex and multifaceted effects. Approximately 75% of subjective effects are, however, attributed to 5-HT2A (Preller et al., 2017).

Lysergamides are among the most potent known psychoactive substances. While most psychopharmaceuticals are dosed in milligrams, lysergamides are active in the microgram range -- one microgram being one-millionth of a gram. For comparison: a therapeutic dose of ibuprofen is 400 milligrams. An effective dose of LSD is 100 micrograms -- that is 4 million times less.

Paradoxically, despite their extreme potency, lysergamides are remarkably low in toxicity. The LD50 (the dose at which 50% of test animals die) of LSD in mice is approximately 46 milligrams per kilogram of body weight -- a purely theoretical, practically unachievable quantity in humans. No verified death from LSD overdose alone is documented in the medical literature (Passie et al., 2008). The therapeutic window is therefore extraordinarily wide.

Lysergamides do not produce physical dependence. There is no withdrawal syndrome, no tolerance escalation in the addictive sense, and no physical craving response. What does occur, however, is rapid pharmacological tolerance: after a full dose of LSD, a second dose the following day is virtually ineffective. This tolerance resolves fully within 5-7 days. This pattern holds for all known lysergamides.

In Germany, the New Psychoactive Substances Act (NpSG) has regulated the handling of substances not listed by name in the Narcotics Act (BtMG) since 2016. The NpSG defines substance groups based on their chemical structure -- and lysergamides are explicitly named as one such group.

This means: when a new lysergamide is synthesised, it may fall under the NpSG if it fits the defined substance group -- even without being mentioned by name. The precise definition of the substance group (annex of the NpSG) determines which structural features are covered and which are not.

For the research community, this carries an important consequence: not every modification to the lysergamide scaffold automatically produces a legal substance. The legal assessment depends on the exact position and type of modification -- and on the current state of the law, which may change.

According to the annual report of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA, 2024), over 30 new lysergamides were identified on the European market since 2015 -- a dynamic landscape that challenges both legislators and researchers alike.

➔ Legality of LSD derivatives in Germany

➔ Albert Hofmann and the discovery of LSD

Let's bring together the key points:

Lysergamides are more than just "LSD and its relatives." They are a chemically fascinating, pharmacologically extraordinary, and historically significant substance class -- from medieval ergot to Hofmann's lab bench to the precisely formulated pellets of today's research community.

Understanding this family means understanding the foundation of what we do as researchers every day. And that understanding -- I am convinced -- makes us better, more responsible researchers.

➔ 1BP-LSD -- the newest family member