Although it occurs naturally in the various strains of “magic” mushrooms that have been growing across the globe since before the arrival of mankind, the psilocybin molecule wasn’t produced in the laboratory until 1958, by the hands of Dr. Albert Hoffman, the same Swiss scientist who first discovered (and tripped on) LSD. A relatively simple molecule in the world of organic chemistry, psilocybin can nonetheless be problematic to synthesize. Dr. David E. Nichols—the professor of medicinal chemistry at Purdue University who whipped up a batch of the stuff for John’s Hopkins recent study—was kind enough to send HIGH TIMES a lengthy email detailing just how tricky and expensive it can be to replicate in the laboratory what nature has already provided.

Although psilocybin is a relatively simple molecule in the world of organic chemistry, it has a couple of features that make it problematic to synthesize. The starting material must be an indole molecule substituted with an oxygen atom at the 4-position. That is the place that will ultimately become the phosphate ester portion of psilocybin. Indole with an oxygen atom at the 4-position is either very costly, or above average in difficulty to make yourself.

Construction of the basic framework of the molecule proceeds in a fairly standard manner once you have the necessary indole in hand. Psilocybin is essentially N,N-dimethyltryptamine (DMT) with a phosphate ester attached at the indole 4-position. Thus, the synthesis is very much like that for making DMT. The product at this stage is DMT with some sort of protected oxygen atom located at the 4-position. We used what is called a benzyl group to protect the oxygen atom. You need to protect it in order to prevent it from participating in the chemistry until it is time for it to be involved at the very end, so to speak.

At the second to last step, you "unmask" the oxygen atom, which leaves a hydrogen attached to the oxygen to provide an OH function, called a hydroxy group.

The most substantial problem occurs when introducing the phosphate ester into the molecule. You must attach the phosphate to the OH group on the indole ring. In Albert Hofmann's original synthesis, he used a reagent to do that which is not available commercially. But unfortunately the reagent itself is unstable, and if you purify it and concentrate it, it can actually explode. Furthermore, the yield, or amount of product you get from that reagent is very low. When you have invested money and effort into making a molecule, you hate to lose most of it at the very end of the process.

Naturally, we did not wish to use that reagent, both for safety and for economic reasons, nor did we imagine that any future manufacturer of psilocybin for medical purposes would wish to use it either. My technician set about examining a large number of methods for attaching phosphate groups to similar OH groups. Finally, we decided to use a material called tetrabenzylpyrophosphate. You can purchase it, but we needed more than we could afford, and so made our own. Importantly, it is a stable white crystalline compound. It allows you to attach a phosphate to the OH, with the phosphate "protected" with two benzyl groups, so the product you obtain is psilocybin, but with two benzyl groups attached to the phosphate oxygen atoms. These benzyl groups come off very easily at the very last step.

So, we used that reagent to attach the dibenzylphosphate to the OH on the DMT skeleton. The chemistry is sensitive here, as you must use a powerful reagent called butyl lithium and keep the reaction cooled to -78 degrees, but we were able to attach the dibenzylphosphate group to the 4-OH group.

In Hofmann's original synthesis of psilocybin, after he put on the dibenzylphosphate group, something happened that even he wasn't aware of. It turns out that because the tryptamine side chain is so cramped for space, so to speak, that it attacks one of the benzyl groups on the phosphate, and a benzyl group moves onto the DMT side chain nitrogen. Because it has the same molecular weight, you can't tell it happened if you analyze the elemental composition, which is what Hofmann did. But the dibenzyl phosphate is a thick liquid, whereas after one of the benzyl groups moves from the phosphate oxygen to the side chain nitrogen, it is a crystalline solid. And that is exactly what Hofmann isolated in his original synthesis.

The same thing happened to us. Unfortunately, we thought that the amine side chain was catalyzing the removal of one of the benzyls by a water molecule, and optimized our synthesis to prevent that from occurring. After we published our work, a Japanese group using our method for putting on the phosphate group got the same crystalline compound. When they looked more closely, they realized the benzyl was just moving over to the side chain nitrogen. They just let the final product stand in solution, so that one of the benzyl groups would completely leave the phosphate and move to the side chain. They crystallized that product, and then removed both benzyl groups: the one remaining on the phosphate oxygen atom, and the one on the side chain amino group.

One new thing we did was to crystallize psilocybin from boiling water. At first it seems counterintuitive, because the conventional wisdom is that psilocybin is very sensitive, but in fact psilocybin is a very stable molecule. We initially were very careful not to heat solutions of psilocybin up, but after several experiments we realized that the molecule is very robust, and ended up obtaining the purest material by recrystallizing it from boiling water to obtain nice white needles.