LSD is arguably the most well-known psychedelic. Yet the precise nature of its synthesis is shrouded in mystery. This is largely due to the fact that manufacturing LSD, compared to other drugs, is not an easy task. The process requires thousands of dollars of laboratory equipment and a strong knowledge base in organic chemistry and lab technique, as well as access to chemicals that the DEA closely monitors. It’s clear, then, that making LSD is not your typical psychonaut hobby project like growing magic mushrooms. This is a guide to the history and science behind LSD manufacturing.
Where Was LSD First Manufactured?
The Swiss chemist Albert Hofmann first synthesized LSD semisynthetically on November 16, 1938, at Sandoz Laboratories. Sandoz was a pharmaceutical company founded in 1886 in Basel, Switzerland. Initially, it was a company that focused on the production of dyes. However, it began producing pharmaceuticals by the turn of the century. In 1917, Sandoz founded its pharmaceutical research department under Arthur Stoll. Stoll was eventually to become Hofmann’s superior in 1929 upon the completion of his doctorate in medicinal chemistry.
Hofmann was systematically investigating medically useful lysergic acid compounds called lysergamides. Lysergamides are amides of lysergic acid that are derived from ergot, a parasitic fungus that grows on rye. As part of a larger research program Sandoz tasked Hofmann with producing pharmaceutical drugs by combining lysergic acid with various organic compounds.
LSD: Not Your Ordinary Ergot Derivative
LSD-25 (an acronym in German for LysergSäure-Diäthylamid-25) was the twenty-fifth lysergamide of the ergot derivatives synthesized in the series. It was produced using the Curtius synthesis, which reacted lysergic acid with diethylamine, an organic derivative of ammonia. Hofmann synthesized LSD in the hopes of obtaining a circulatory and respiratory stimulant. But the compound was set aside when animal studies demonstrated it did not have the sought-after effects.
However, Hofmann decided to revisit the compound five years later. In the process of its synthesis, he accidentally absorbed a small amount through his fingertips, thereby embarking on the first-ever acid trip. With its psychoactivity unveiled, further research would demonstrate LSD’s tremendous psychiatric and medicinal uses. Starting in 1947, Sandoz Laboratories began to manufacture and distribute LSD to researchers and physicians under the trade name Delysid. This continued throughout the ’50s and early ’60s until LSD swept through the counterculture, eventually leading Sandoz to halt production in 1965.
LSD’s proliferation among the general public in the late ’60s is largely due to its underground production by a handful of individuals, including Tim Scully, Owsley Stanley, and Nick Sand. By the turn of the century, LSD availability significantly declined as manufacturing sources dried up. Most notably, this was due to the arrest of Nick Sand and William Pickard, the latter of whom allegedly produced approximately 90% of the world’s LSD, according to the DEA. Nowadays, mostly professional chemists make LSD in a handful of clandestine labs.
The LSD Molecule & Chemical Structure
The LSD molecule consists of a tetracyclic ring structure with a tryptamine core. The tryptamine core consists of an indole ring system, which is a 6-membered benzene ring fused to a five-membered nitrogen-containing ring. This structure is found in other serotonergic psychedelics such as ibogaine and psilocybin, as well as the endogenous neurotransmitter serotonin.
LSD has four different isomers, that is, compounds with the same chemical formula that differ in the spatial arrangement of their atoms. These are d- and l-LSD as well as d- and l-isoLSD. However, only d-LSD has psychoactive properties, so the last manufacturing steps involve purifying this specific isomeric form. Once purified, LSD is a white, odorless crystalline powder that dissolves easily in water.
LSD is part of a class of compounds derived from ergot called ergolines. Therefore, its chemical structure closely resembles other ergoline derivatives, such as ergine (LSA), and the uterotonic drugs ergonovine and methergine. Like LSD, all of these compounds are amides of lysergic acid.
Lysergic acid is a precursor compound to a wide array of ergoline alkaloids. It is fundamental to the production of LSD under many synthesis routes, and for this reason, it is listed as a Schedule III controlled drug. The name lysergic acid is derived from how it’s produced, via the lysis of ergot alkaloids.
Chemists make lysergic acid by treating the ergot alkaloids produced by the ergot (Claviceps purpurea) fungus with a strong base, such as lye or potassium hydroxide. They then carefully neutralize the basic mixture with an acid. The strong alkali cleaves the amide linkage of the ergot alkaloid, producing lysergic acid. Lysergic acid can also be produced by extracting ergine (d-lysergic acid amide) from Hawaiian Baby Woodrose or Morning Glory seeds, and treating the purified extract in the same manner as the aforementioned ergot alkaloids.
The carboxylic acid group (-COOH) of lysergic acid reacts with an amine, forming the corresponding amide. While the reaction with diethylamine produces lysergic acid diethylamide, lysergic acid can react with numerous other amines, including dimethylamine, dipropylamine, dibutylamine, and many more. The amides formed by these amines show only a small fraction of the potency of LSD, which signals that the diethylamide group is central to LSD’s psychoactive potency.
Iso-Lysergic Acid Hydrazide
When producing LSD from ergot alkaloids, the first step often involves the production of a lysergic acid compound called lysergic acid hydrazide. The chemical structure of lysergic acid hydrazide is highly similar to lysergic acid, except a hydroxy (OH) group is replaced by a couple of nitrogens that are attached to 3 hydrogens (N2H3).
Makers create this intermediate because it is more stable than the free lysergic acid, and is, therefore, a better starting product. In addition, extracting it away from the other irrelevant compounds found in the starting material results in a much purer final product.
How to Make LSD: Key Procedures Explained
Today, a wide variety of synthesis routes are available for the acid chemist. Broadly categorized, these are either semisynthesis or total synthesis. A semisynthesis starts with natural precursors (like ergotamine) and typically has just a few major steps.
On the other hand, a total synthesis starts from simple precursors without the aid of biological processes. The total synthesis of LSD is much more complicated, and can easily have over 15 steps depending on the method.
The following breakdown is a high-level overview of the procedures that Stoll and Hofmann used and reported in the first synthesis of LSD in 1943.
Step 1: Convert Ergot Amides to iso-Lysergic Acid Hydrazide
The semisynthesis of LSD begins with an ergot alkaloid like ergotamine. Ergine can be extracted from the seeds of Morning Glory and Hawaiian Baby Woodrose and utilized as well, but it’s not typically used as the starting material because of poor final yields.
The most common starting material, ergotamine, is a controlled and closely monitored substance that’s not readily available in the United States. With that said, some small-batch chemists have extracted ergotamine from a migraine headache medication called Cafergot, which contains caffeine and ergotamine tartrate.
First, they combine ergot amides with anhydrous hydrazine under heat with water to form lysergic acid hydrazide. Anhydrous hydrazine is a solvent that’s extremely poisonous and carcinogenic. It’s also combustible and may lead to an explosion when it’s not distilled under a nitrogen atmosphere.
In the simplest synthesis, this reaction produces primarily the iso form, which must be later converted to the active form under an alkali environment.
Step 2: Convert to Lysergic Acid Azide
Under a red light and at 0°C, lysergic acid hydrazide is converted to lysergic acid azide by the addition of sodium nitrite (NaNO2). A base neutralizes the stirred solution, which is then extracted with a solvent. The result is a yellow azide.
An azide is a functional group with a chemical formula of N3. Transforming the hydrazide into the azide activates the carboxyl group on the lysergic acid, which allows it to readily react with an amine in the next step (i.e., it’s a good leaving group).
Step 3: Form iso-Lysergic Acid Diethylamide
Next, chemists dissolve the azide in diethylamine ((CH₃CH₂)₂NH) animates it. They heat and evacuate the solution in a vacuum after it has stood in the dark for a day. The result is the inactive iso-lysergic acid diethylamide. They must then convert this into the active lysergic acid diethylamide.
Step 4: Purify and Separate Isomers
The inactive iso-LSD is converted into active LSD through a process called isomerization. Chemists add the iso form to some alcoholic potassium hydroxide (KOH) under heat. They neutralize the solution with an acid.
The solutions is then basified, extracted with chloroform, and evaporated under a vacuum. This results in a mixture which is roughly two-thirds active form LSD and one-third iso-LSD.
The product is then purified a final time via column chromatography over alumina. As the solution drains through the column, active lysergic acid diethylamide elutes from the column as a blue band under long-wave ultraviolet light.
Step 5: Crystallize and Dose LSD-25
The chemists then collect and evaporate the above fraction of active LSD-25 in a vacuum. It has a syrupy consistency that spontaneously crystallizes. It is typically formed into the tartrate salt by adding the LSD to a tartaric acid solution in methanol. Upon recrystallization, this forms a much more stable end product. However, the compound is still highly sensitive to degradation by heat, light, oxygen, and chlorine.
From here, chemists dose the LSD by dissolving the tartrate salt in water or alcohol. They dip sheets of blotter paper into the solution and dry them. These perforated sheets contain over 1000 ¼” squares, or “tabs,” each of which contains a dose of approximately 100 micrograms. Due to its extreme sub-milligram potency, relatively small amounts of ergoline precursors can end up supplying large amounts of the global LSD market. Just 25 kilograms of ergotamine can produce 5–6 kilograms of LSD, corresponding to some 100 million doses.
- Psychedelic Chemistry by Michael Smith
- Practical LSD Manufacture by Uncle Fester
- TIHKAL: The Continuation by Alexander and Ann Shulgin
Disclaimer: LSD is potentially categorized as an illegal drug. Reality Sandwich is not encouraging the use or making of this drug where it is prohibited. However, we believe that providing information is imperative for the safety of those who choose to explore this substance. This guide is intended to give educational content and should in no way be viewed as medical recommendations.
RS Contributing Author: Dylan Beard
Dylan Beard is a freelance science writer and editor based in the beautiful Pacific Northwest. After finishing his physics degree and dabbling in neuroscience research at UC Santa Barbara in 2017, he returned to his first love: writing. As a long-term fan of the human brain, he loves exploring the latest research on psychedelics, nootropics, psychology, consciousness, meditation, and more. When not writing, you can probably find him on hiking trails around Oregon and Washington or listening to podcasts. Feel free to follow him on Insta @dylancb88.