An Introduction to Psychedelic Tryptamine Chemistry (For Non-chemists)

This article is intended for the general reader that have an appreciation for the beauty of chemistry, and/or desire to learn more about it. That being the case I am going to be somewhat pedantic throughout the articles, deconstructing technical terms and “dirty pictures”¹ with the assumption that you do not know what they mean. In this way we can learn them as we go along. If you are already fluent in Chemistrian, it goes without saying that you are free to skip over these and peruse selectively.

The Three Main Classes of Psychedelics
There are three classes to which nearly all psychedelic compounds belong — the tryptamines, phenethylamines, and ergolines (Figure 1).

1. The tryptamines include most of the well-known naturally-occurring psychedelics, including compounds derived from entheogenic fungi (psilocybin and psilocin), DMT, 5-MeO-DMT, bufotenin, and ibogaine.
2. Mescaline is the only common naturally-occurring phenylethylamine, yet the class includes numerous well-known synthetic compounds such as MDMA and the 2-C’s.
3. Ergolines most notably include the naturally-occurring LSA and the semi-synthetic compound that turned on a generation, LSD.

Tryptamines
 Psychedelics of this class are all derived from tryptamine (Figure 2), a ubiquitous endogenous ligand and agonist of the human trace amine-associated receptor 1 (TAAR1). The name tryptamine is derived from its structural similarity to l-tryptophan (Figure 3), an essential amino acid and the precursor to both serotonin and melatonin.

Substituted Tryptamines
 Although the “template” for psychedelics tryptamines is the molecule with all the various positions presented in Figure 2, in actuality there are limitations to how this manifests. This is because certain modifications are difficult to impossible, or even if the do occur, lead to inactive compounds. For example if something is attached to position 2 (Figure 2) the compound becomes a serotonin-2A receptor antagonist, therefor losing its psychoactivity. Based on these restrictions we can simplify the template presented in Figure 2 to Figure 4, which is called the ‘substituted tryptamine’.

By using this figure as a roadmap we can explore the three main changes that synthetic chemists can make to derive psychedelic analogs.

1. One can add side chains to either position 4 or 5, and those side chains have to contain an oxygen molecule. We can confirm this by looking at all the well known psychedelic compounds that have side chains attached to these positions:
   - Bufotenine has a hydroxyl (OH) group at position 5, 
   - 5-MeO-DMT has a methoxy (O-CH3) at position 5, 
   - Psilocin has a hydroxyl (OH) group at position 4, and 
   - Psilocybin has a phosphoryloxy (OPO3H2) at position 4.
2. One can methylate (add a methyl group) to the alpha-position to change a non-orally active species into one with oral active.
3. One can add a sidechain to positions N1 or N2. All five of the major naturally-occurring species we mentioned in point 1 possess methyls at both positions (hence “dimethyl” from which the DM in DMT is derived — more below). These methyls may be substituted with more complex alkyls, another way in which chemists can turn non-orally active tryptamines into orally active species.

Psychedelics Tryptamines
Now that we have an idea of the chemical “archetype” of tryptamine psychedelics and the possible changes chemists can make, let’s have a look at the five most well-known naturally-occurring examples: DMT, 5-MeO-DMT, bufotenin, psilocybin, and psilocin.

DMT
 The substitutive name for DMT is N,N-dimethyltryptamine. One of the most magical parts of learning the chemical language is that from it one can deduce what they actual molecule looks like, and vice-versa.

Let’s explore that by using DMT as an example. Starting from the back we have tryptamine (blue), so we know that is the foundation of our molecule — the indole ring with an ethyl in position 3 attaching to an amine. Then we have “dimethyl” (red), meaning two methyls. Okay so now we know it’s the tryptamine molecule that has two methyls added to it. And where are these two methyls? They’re both positioned on the nitrogen of the amine, hence ‘N,N’.

What’s more is that N,N-dimethyltryptamine forms the foundation for all four other compounds we are going to discuss. In other words, all four of them are N,N-DMT with a little something extra. We can see that because the term is contained within the substitutive name of all four other molecules.

5-MeO-DMT
 The substitutive name for 5-MeO-DMT is 5-methoxy-N,N-dimethyltryptamine (Figure 6). We can see that it has the whole name of DMT in it, so when we draw it we know we can start with that molecule — a tryptamine with two methyls on the amine (red and blue). What’s left is ‘5-methoxy’, which means that at position 5 we have a methoxy (green). A methoxy is a combination of a methyl and an oxygen.

Bufotenin
 The substitutive name for bufotenin is 5-hydroxy-N,N-dimethyltryptamine (Figure 7). As was the case with 5-MeO-DMT, the molecule has DMT as a starting point (red and blue). But this time, instead of a methoxy at position 5, we have a hydroxy, -OH (green).

Psilocin
 The substitutive name for psilocin is 4-hydroxy-N,N-dimethyltryptamine (Figure 8). Same story, it starts with the structure of DMT (red and blue). If we compare them, we can see the psilocin is extremely similar to bufotenin, the only difference being that where bufotenin had the hydroxy at position 5, here it’s at position 4 (green).

Psilocybin
 The substitutive name for psilocybin is 4-phosphoryloxy-N,N-dimethyltryptamine (Figure 9). By now I’m sure you’ve grokked it — it’s a DMT molecule (red and blue) with a little something extra. As with it’s cousin psilocin, that something extra is at position 4, but instead of a hydroxy, it’s a phosphoryloxy with the composition OPO3H2 (green).

All five molecules and their substitutions are reviewed in Figure 10 below.

In the next article in this series I discuss how synthetic chemists can alter tryptamines like DMT or 5-MeO-DMT to give them oral activity.

1 = Sasha Shulgin used to affectionately refer to organic molecule structures as “dirty pictures”.