LSD is a popular hallucinogenic drug, usually called "acid" on 'the street.' There are a number of popular myths within the drug-using culture about the manufacture of LSD which are easily contradicted. The myths I'm specifically interested in contradicting are:
1) It requires a PhD in synthetic organic chemistry to be able to make LSD.
2) LSD synthesize requires over twenty thousand dollars worth of equipment to make.
3) An LSD synthesis is extremely complicated and high tech.
Comments on the myths:
1) LSD was first synthesized in 1938. A PhD in chemistry will prepare you for 21st century chemistry, which is far ahead of the chemistry of the 1930s. While the inventor, Albert Hoffmann may have had a PhD, he was the first to make LSD ever. Making a known substance, by a known procedure devised almost 70 years ago does not require a PhD. Also, based on the numerous syntheses of other known controlled drugs, LSD is relatively easy to make by comparison.
2) The document below will show that it would be reasonable to estimate that the total cost of an LSD synthesis could be acheived with under a thousand dollars of equipment.
3) The processes involved in an LSD synthesis could be demonstrated to a teenager in an hour. The procedures carried out are usually performed in second year undergraduate labs in organic chemistry courses. An average undergraduate at their third year of study should be able to read and fully understand an LSD synthesis.
With all of that being said, what follows is essentially a cut and paste of patent documents detailing the synthesis of LSD. I obviously advise anyone reading this NOT to follow any procedure below, as synthesizing LSD without permission of the relevant regulatory agency is probably criminal, no matter where you live in the world. Attempting to synthesize LSD can land you in jail for a long time, so don't be stupid and try this at home.
In all chemical transformations listed herein, reactions will still proceed successfully whether or not the reactant is racemic or not, or is isomerized (bears the "iso" prefix) or not.
For example, Step 1 of the main procedure will produce racemic lysergic acid hydrazide and racemic isolysergic acid hydrazide, which are used in step 2 (even though the example in step 2 uses d-isolysergic acid hydrazide). The crucial thing to bear in mind is that the l- isomers will always produce l-LSD, which is waste. Hence, one can use racemic hydrazides in step 2 and isolate the d- isomers later or one can first isolate the d- hydrazides first and use those in step 2. The former is the first procedure given here and the latter corresponds to the alternative procedure listed below.
Parts are given as proportions by weight.
A number of lysergic acid derivatives, such as lysergic acid amides and esters, as well as the lysergic acid derivatives found existing as ergot alkaloids are suitable for preparation of the hydrazide. Appropriate substitutions for the starting material in step 1 can be made. See GB Patent 463936 for details.
5 parts of a non-crystallizable crude product obtained from the mother liquors of ergotamine extraction are suspended in 30 parts hydrazine hydrate and heated for 5 hours in a closed vessel and under pressure* at 115 C. After separation from the insoluble products the brown hydrazine solution is concentrated to about 10 parts and left to stand in a cool place, whereby the lysergic acid hydrazide separates out as a grey crystalline powder which, after recrystallization from ethanol, is obtained in quite a pure state.
- Note: pressure is not necessary. Appropriately modifying the procedure below will work. For example:
When 1 part of a mixture of ergotamine and ergotaminine is dissolved in 5 parts propyl-alcohol and 5 parts hydrazine hydrate are added, the mixture is heated to boiling for 10 hours under a reflux condenser. After concentration of the solution in vacuo, the hydrazide is isolated with a yield of 0.2 to 0.3 parts.
Step 2: Azide Preparation
3.0 grams of d-iso-lysergic acid hydrazide are converted into the azide in the known manner with sodium nitrite in hydrochloric acid solution at 0 C, the acid solution neutralized with sodium bicarbonate and the azide extracted with 300 cc. of ether.
The azide is used immediately in step 3.
Step 3: LSD and isoLSD
3.0 grams racemic isolysergic acid hydrazide** are converted into the azide in the known manner and then separated in voluminous light yellow flocks by stirring in an excess of sodium bicarbonate solution, thoroughly filtered off by suction and immediately added at -5 C to a cooled solution of 3 cc diethylamine in 30 cc of alcohol, whereby the azide rapidly dissolves. The brown solution is slowly warmed to 30 C, maintained at this temperature for 1 hour and then the solvent evaporated off in a vacuum. The pasty residue is rubbed with 30 cc of water and filtered with suction. Yield: 2.8 g of racemic LSD and isoLSD combined (about 0.7 g is d-LSD). To obtain crystals, dissolve in methanol and add approx. 1.5 g of tartaric acid (or equivalent of weak organic acid such as ascorbic acid) and remove the solvent in vacuo. If separation of LSD from isoLSD is desired, see the following instructions.
Chromatographic Separation of Lysergic and Isolysergic Isomers
After rinsing the pasty residue with water and filtering with suction, the crude condensation product, 2.8 grams, which consists of racemic diethylamide of isolysergic acid and racemic diethylamide of lysergic acid is chromatographically separated with aluminium oxide as adsoprtion column using chloroform containing 0.5% alcohol as the solvent. Two main zones are formed having a blue fluorescence in ultra-violet light of which the quickly moving one contains the racemic diethylamide of lysergic acid whereas the more firmly held fraction consists of the racemic diethylamide of isolysergic acid.
Specifically: The mixture is dissolved in a little chloroform which contains 0.5% of alcohol, the solution poured on to a column of aluminum oxide of 4 cm diameter and 60 cm length and the chromatogram is produced with the same solvent. Dark impurities soon pass into the filtrate. Then follows a broad zone appearing blue in ultra-violet light which contains the diethylamide of d-lysergic acid. Yield 1.0 to 1.3 grams. The d-isolysergic acid diethylamide passes through much more slowly. (yes, this works with the racemic compounds or with the d- isomers)
Isolation of d-LSD from d,l-LSD
From the racemic diethylamide of lysergic acid the diethylamide of d-lysergic acid can be separated e.g. by means of the neutral tartrate. For this purpose, 3.2 grams diethylamide of racemic lysergic acid (1/100 mol.) are dissolved in 6 cc methanol and treated with 0.75 grams d-tartaric acid (1/200 mol.) in 2 cc of the same solvent. By inoculation with the d-tartrate of the diethylamide of lysergic acid this crystallizes in almost colourless needles united in bundles. Yield 1.0 to 1.2 grams.
Conversion of d-isoLSD or d,l-isoLSD to d-LSD and d,l-LSD respectively
General procedure: The diethylamide of d-isolysergic acid is converted into the diethylamide of d-lysergic acid according to the processes usual with ergot alkaloids, namely by treating them with acid or alkaline comounds. By allowing the iso compound to stand with diluted alcoholic potash for example an equilibrium is soon formed which consists of approximately equal quantities of the lysergic acid and the isolysergic acid compounds.
- Below is a list of starting hydrazide and % parts yield (by parts d-LSD/parts hydrazide used)
as (hydrazide used, % by weight d-LSD recovered)
Starting hydrazide: 1) d-isolysergic-, 33-43% 2) d-lysergic-, 43-57% 3) racemic isolysergic-, 22-27%
It seems the isomerization at C5 only occurs with hydrazide production and does not occur further with transformation to the azide or diethylamide and this is consistent with the literature (Garbrecht, 1959). Hence, one must avoid using l-isolysergic or l-lysergic isomers after hydrazide preparation if the desired product is d-LSD, the active product. Since transformation to the hydrazide results in racemic d- and l- isomers of both the lysergic and isolysergic form, 50% of the starting ergot alkaloid material will be converted to the useless l- isomer. This is unavoidable with this method.
At the end of step 3, one has an essentially equal mixture of d-LSD, l-LSD, d-isoLSD and l-isoLSD. d-LSD is the active product and the other isomers are not known to be active. Hence, this is where the ease and convenience of this method becomes apparent. When measuring out samples for biological assays, the investigator must simply bear in mind that only 1/4 of what is being weighed is active. Many investigators would likely prefer to work with the pure, active isomer, d-LSD and thus instructions for its isolation have been included.
This alternative procedure is essentially the same as above, except that following preparation of the hydrazide, the d-(iso)lysergic acid hydrazide is isolated. Recall that it is crucial to obtain and use the d- isomers, but whether or not it is d-lysergic acid hydrazide or d-isolysergic acid hydrazide is unimportant. Step 3A ("A" for "alternative") corresponds exactly to Step 3 above and is included as an example.
Step 1: (As above)
Step 2: Isolation of the D- Hydrazide
2.820 g (1/100 mol.) DL-isolysergic acid hydrazide are dissolved under reflux in 1200 cc. of methanol. 3.14 g of (1/100 mol.) of di-(beata, beta-dimethylacroyl)-L-tartaric acid dissolved in 400 cc. of methanol are added to the clear solution and the mixture is further boiled for 15 to 30 minutes. The solvent is then distilled off, preferably under normal pressure, rapidly until only 200 cc are left, the solution is cooled in a stream of water and thereupon D-isolysergic acid hydrazide-L-(di-dimethylacroyl)-bitartrate begins to crystalize out in white needle clusters. The crystallization is completed by allowing it to stand for 3 to 4 hours at room temperature and then for a further hour in ice water. The salt is then separated by suctional filtration, washed with a little methanol and dried in vacuo. The yield is 2.5 to 2.8 g of D-isolysergic acid hydrazide-L-(di-dimethylacroyl)-bitartrate. In order to recover the free D-isolysergic acid hydrazide, the salt derivative is finely powdered and suspended in a water immiscible organic solvent, for example ether, benzene, chloroform or ethyl acetate and decomposed with sodium or potassium bicarbonate. After filtering and thereafter carefully distilling off the organic solvent phase under reduced pressure, D-isolysergic acid hydrazide of a considerable degree of purity remains behind as a yellowish white residue from the evaporation. It can be recrystallized from methanol.
More than just this one tartaric acid derivative can be used for this separation, but I refer you to the patent for details. Also note that the main procedure simply uses tartaric acid, as opposed to a tartaric acid derivative, in order to isolate d-LSD, so this alternative procedure doesn't really offer any benefits. Step 2 of this procedure should also be used on D,L-lysergic acid hydrazide to obtain D-lysergic acid hydrazide, which would then be used in step 3.
Step 3A: [Azide Preparation is included in this step]
3.0 grams of d-iso-lysergic acid hydrazide are converted into the azide in the known manner with sodium nitrite in hydrochloric acid solution at 0 C, the acid solution neutralized with sodium bicarbonate and the azide extracted with 300 cc. of ether. 3 cc of diethylamine are added to the ethereal solution which has been dried for a short while with freshly ignited potassium carbonate and it is allowed to stand in the dark at room temperature for 24 hours with occasional shaking. The ether, from which a little dark oil has separated, is evaporated off in vacuum and the residue thereby obtained rubbed with 30 cc. water and filtered off with suction. The dark amorphous product consists approximately of equal parts of the diethylamide of d-lysergic acid and the diethylamide of d-isolysergic acid.
For the isolation of d-LSD see above (Chromatographic Separation of Lysergic and Isolysergic Isomers).
- In Step 1 of the main procedure, the crude alkaloid extract was determined to contain ergot alkaloids by a positive colour test by Keller's reaction. See the patent referred to in Step 1 for details.
Procedures Taken From the Following References
GB Patent 463936. The Preparation of Lysergic Acid Hydrazide. April 8, 1937. GB Patent 579484. Process for the Preparation of Diethylamide of d-Lysergic Acid. August 6, 1946. GB Patent 788416. Process for the Resolution and Recovery in the Pure State of Hydrazides and Amides of DL-Lysergic Acid or DL-Isolysergic Acid. January 2, 1958.
Garbrecht, WL. Synthesis of Amides of Lysergic Acid. Journal of Organic Chemistry. 24, pp. 368 - 372. (1959)