Any hobbyist can grow psilocybin mushrooms or marijuana plants. LSD, however, can only be produced by skilled, highly trained chemists. In this article, we provide some insight into how LSD is produced.
LSD1 is in a diverse group of chemicals called ergoline derivatives that includes drugs capable of increasing blood pressure, helping with migraines and treating Parkinson’s disease. These chemicals all share a common molecular skeleton made up of four rings called ergoline.
There are many methods that can be used to synthesize LSD. It is technically possible to start with common materials like, ammonia and carbon monoxide, and produce large quantities of high purity LSD. However, this type of total synthesis from scratch would take a long time and a large amount of starting materials. It is always more practical to begin working with starting materials that are more structurally similar to LSD.
Many of the molecules that can be useful for synthesizing LSD also have psychedelic activity and are also regulated as controlled substances. For example, lysergic acid amide is a useful precursor that has psychedelic activity and can be extracted from seeds from plants of the Convolvulaceae family. Consequently, it is listed as a Schedule III controlled substance.2 Some useful starting molecules are not directly regulated as controlled substances but instead tracked as immediate precursors.3 For example, a molecule known as ergotamine is listed as a DEA List I chemical precursor because it’s utility in manufacturing LSD.4 Adding a chemical to List I adds various forms of control and regulation, including the requirement that all sales must be reported to the DEA.
LSD was discovered in the late 1930s when Albert Hoffmann was purifying and synthesizing the active ingredients in an ergot fungus. Starting from plant and fungi based chemicals is still a method that is employed today. Alternatively, over the decades, dozens of completely synthetic reactions have been devised to create LSD from precursor chemicals that are readily available. Finally, research chemicals exist which may be legally obtainable for research purposes and have a similar structure to LSD, making them potentially useful as a precursor.
Synthesis from ergot alkaloids
LSD synthesis can start from precursor chemicals called ergot alkaloids. Alkaloids are just chemicals that include a particular arrangement of carbon and nitrogen molecules. There are three main sources of ergot alkaloids when producing LSD today:
- Ergotamine is produced by several fungi in the Clavicipitaceae family. About 2% of the dry mass of the ergot fungus Claviceps purpurea, one of the most common sources, is made up of ergotamine. This fungus also contains trace amounts of lysergic acid, a closer precursor to LSD, but no actual LSD at all.5 Consumption of the ergot fungus can lead to a disorder known as ergotism, so isolation and purification of the chemical is required. Ergotamine is a List I chemical and its manufacture and distribution is monitored by the DEA.
- Ergotamine tartrate
- A prescription medicine known as cafergot is composed of caffeine and ergotamine tartrate (a salt form of ergotamine). Synthesis from these tablets involves converting the ergotamine tartrate salt into the ergot alkaloid. A popular synthesis method known as the Shulgin method exists that has since been tailored to start from this precursor.6
- Ergine (Lysergic acid)
- Ergine is produced by several vines in the Convolvulaceae family and various fungi. Seeds from ololiuhqui (Turbina corymbosa), Hawaiian baby woodrose (Argyreia nervosa) and morning glories (Ipomoea tricolor) have been used for their psychedelic activity themselves. In the US and many other countries, morning glory seeds are coated in toxins partly to discourage their consumption for recreational purposes. In addition to ergine, seeds from many of these vines also contain trace amounts of lysergic acid. Both ergine and lysergic acid have psychedelic activity and are listed as Schedule III. While possessing the seeds is legal, isolation and possessing either ergine or lysergic acid would likely be illegal.
Either ergotamine or ergine must first be isolated and purified. Once this is done, the ergot alkaloid can be taken through a type of reaction called hydrolysis that will result in lysergic acid as a product. Alternatively, synthesis reactions exist to go directly to LSD without stopping to isolate and purify lysergic acid.7
Total synthesis from commercially available precursors
Over the decades, multiple approaches have been devised to synthesize either lysergic acid and LSD directly without the need of starting from an ergot alkaloid.8 9 10 These methods typically depend on exotic techniques and/or laboratory equipment, but have the advantage of not requiring LSD-specific precursors. Because the equipment is highly specialized, these total synthesis techniques are not particularly useful for a small production.
Synthesis from lysergic acid
Regardless of the route, many synthesis reactions aim to produce lysergic acid as their end-point. From here, there are straight-forward approaches to converting the compound to LSD. Most commonly, lysergic acid is activated using a peptide coupling agent along with a compound like phosphoryl chloride.11 12 Once activated, diethylamine is added to complete the molecular change to LSD. Diethylamine is used in a variety of industrial processes but it also listed as a Special Surveillance chemical by the DEA. This requires manufacturers to practice “Know your customer” techniques to attempt to determine if the compound is being used illegally by any buyer.
Synthesis from related research chemicals
In theory, taking a currently legal research chemical and converting it to LSD could be a more straightforward approach to producing LSD than starting from other less similar precursors. However, there are no published synthesis reactions describing this process. This is likely complicated because the legal status of many research chemicals is uncertain as they can be added as a controlled substance under the Federal Analogue Act.13 However, there is evidence that some of the research chemicals are actively transformed into LSD after ingestion. For example, scientists were able to identify LSD molecules after 1P-LSD was left in human serum.14 This indicates the feasibility of converting 1P-LSD directly into LSD.
The actual chemical reactions that need to be performed to create LSD are straight-forward. Given the appropriate laboratory equipment and sufficient precursors and reagents, a competent chemist could safely create a lifetime supply of LSD within a couple of weeks.
Knowledge of fundamental chemistry concepts, especially organic chemistry synthesis is required. For example, the ability to calculate and accurately measure molarity of various compounds is required in every synthesis approach.
Another important component is the ability to perform the organic chemistry laboratory techniques required by each synthesis. This includes the ability to dry liquids over a vacuum, refluxing under an inert atmosphere, isolation by chromatography. These techniques require training and practice to be able to work competently. In addition to techniques that influence the yield of product, many of the chemicals used are hazardous. Basic safety techniques are essential when using these as exposure to skin or inhalation can be fatal.
Access to the appropriate laboratory equipment is also required. Every synthesis approach requires some level of controlling the environment around the chemicals being reacted. This can include restricting the color of light, removing oxygen from the atmosphere, or just controlling temperature. In addition, glassware and other apparatus need to be properly sterilized. While these all can be hacked in some way, the use of specialized equipment allows more precise control that ultimately affects the end yield of product. There also exists optional equipment that would greatly facilitate the process. For example, performing these reactions in a fume hood with a vacuum and appropriate safety equipment is not strictly required but would make the process significantly faster and much safer. Finally, some of the total synthesis reactions require access to exotic laboratory equipment.
Number of people
All of the organic chemistry techniques employed in the synthesis reactions can be performed by a single competent person. As with most chemistry techniques, proper planning of each step ensures that every reaction and product will be exposed to the correct environment and have sufficient time to move to the next step. For a smaller setup, a single competent person is more than sufficient to complete all steps. Having a single established partner may speed up the process.
Amount of time
Each synthesis technique involves different steps which can affect the total amount of reaction time. Some steps require time to process and cannot be sped up. For example, isolating compounds in a chromatography column can easily take anywhere from 2-3 hours to overnight to allow compounds to settle. Similarly, time is affected by the equipment available. For example, evaporating liquid solutions can take an hour over vacuum, or overnight (or more) without.
For many of the synthesis reaction starting from an ergot alkaloid, it should be possible to complete the entire reaction, producing relatively pure LSD within three days. Taking a more relaxed and non-optimal approach, all steps could be completely easily within a week.
The amount of LSD produced is largely tied to the amount of precursor and/or any controlled or regulated reagents that can be obtained.
It may be useful to look at a test case of producing LSD from a bottle of 100 tablets of cafergot, a typical prescription size. Each tablet has approximately 2mg of ergotamine tartrate that would yield approximately 100mg of ergotamine once isolated and purified. After going through a synthesis reaction7, there would be an effective expected yield of nearly 19 mg of LSD. A typical single blotter hit has 150 micrograms of LSD. Therefore this reaction would result in 126 hits. More recent doses for single hits have falled to 20 micrograms, which would allow the creation of 950 hits, more than a single blotter paper, from the 100 cafergot tablets.
A larger setup with bulk levels of precursors and reagents could generate much more. This is probably best exemplified with the arrest of Leonard Pickard and Clyde Apperson in 2000. The DEA suggested that 41.3 kg of LSD were seized and that the two chemists were producing a kilogram of pure LSD every 5 weeks. This claim has come under scrutiny15, and the DEA has since removed their press release.16
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Nichols DE, Frescas S, Marona-Lewicka D. Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD). J Med Chem. 2002. 45(19):4344-9. ↩
Brandt SD, Kavanagh PV, Westphal F. Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD). Drug Test Anal. 2016 8(9):891-902. ↩