Psychedelic Tryptamines
Tryptamine chemistry is intricately intertwined with the functioning of not just our minds, but the minds of most creatures that have a brain. Tryptamine, a derivative of the amino acid tryptophan, is hydroxylated to produce the neurotransmitter serotonin.
Serotonin has functions throughout the body, especially in the enteric nervous system, on platelets in blood, and in the brain. Serotonergic neurons in the brain primarily originate in the Raphe Nuclei projecting outwards to other parts of the brain, such as cerebellum, spinal cord, hippocampal structures, the amygdala, and the neocortex.
N,N-Dialkyl Tryptamines
The basic substructure of the psychedelic tryptamines is the indole nucleus. Tryptamine is just an indole nucleus substituted at the number 2 position with an ethylamine group. Many variations based on this simple structure are possible, with almost all of the psychoactive indoles having an di-substituted (generally di-alkyl) ethylamine at number one position. The simplest psychedelic tryptamine is DMT - dimethyltryptamine, with two methyl groups attached to the terminal amine nitrogen. This naturally occuring tryptamine (occuring both in many species of plants as well as being naturally produced in the brain) is an extremely potent, but short acting, psychedelic drug.
Further modification to the terminal amine by changing the substituents on the terminal amine to various mixtures of methyl, ethyl, propyl, or isopropyl groups, almost always by di-substituting it, creates an entire series of DMT analogs. Comparison of this series of N,N dialkyl tryptamines produced this order of activity: methyl,isopropyl tryptamine (MIPT) > methyl,ethyl (MET) > dimethyl (DMT)> methyl, n-propyl (MPT) > diethyl (DET) > diisopropyl > di-n-propyl (DPT) > methyl, tert-butyl > (MTBT)
Unsymmetric substitutions such as methylisopropylamine are the most active and orally bioavailable. In General, in any series of tryptamines, changing the N,N substituents while keeping all other things the same will result in a series with a similar order of potency. The alkyl groups on the terminal nitrogen mostly have the effect of altering bioavailablity and potency.
Other Substitutions on the Tryptamine Structure
Leaving the terminal amine constant, other modifications can be made to the tryptamine molecule, most commonly by adding to the number 4 or 5 position of the indole ring. These changes affect the potency of the drug, but more interestingly, they alter the character of it’s psychoactivity. Generally, these 4- or 5- substituted tryptamines also have some sort of N,N-dialkyl subtituents as well, most commonly dimethyl (DMT series), diisoproply (DIPT series), or methylisopropyl (MIPT series) groups on the terminal amine.
4-Substituted dialkyltryptamines
4-substituted tryptamines generally have a loss in potency (per mg) compared to their 4-unsubstituted cogeners, but are much more psychedelic than non-substituted or 5-substituted N,N-dialkyl tryptamines. Substituents generally contain an oxygen atom, and can be hydroxy or acetoxy groups. The 4 hydroxy tryptamines include psilocybin/psilocin, 4-OH MIPT, 4-OH DIPT, etc. These are more psychedellic and produce more visual hallucinations than their non-4-substituted brothers, or 5-substitued, but may require higher doses for activity. 4-hydroxy or acetoxy sub’d tryptamines (such as psilacetin (4-acetoxy-dimethyltryptamine (4-Aco-DMT), or psilocybin (4-Hydroxy-DMT) are great.
4-methoxy DMT breaks this rule and is not as active and is less psychedelic than the other 4-subed tryptamines because the methyl group hides the oxygen atom, inhibiting it’s interaction with a hydrophilic site on the serotonin receptor it is believed. In contrast, an acetoxy group at the 4 position (such as 4-Aco DMT (Psilacetin, a psilocybin precursor) do not have this loss of potency, possibly because it retains some hydrophilic character as it is also electron/oxygen rich. It may also be that it is the deacetylated metabolite (which would be 4-hydroxy) is the active molecule and 4-acetoxy is just a prodrug (much the same way that heroin is just an acetoxy derivative of morphine, and is rapidly deacetylated to morphine, which is responsible for most of the actions of heroin).
5-Hydroxy Tryptamines
Serotonin is a 5-Hydroxy-Tryptamine (hence it’s abbreviation 5-HT). However, the terminal amine of serotonin is non-substituted, and it is very rapidly metabolized and cleared out of the synaptic cleft by both monoamine oxidase A, COMT (another enzyme that metabolizes monamines, as well as the serotonin reuptake pump.
The di-alkyl derivatives of 5-hydroxy Tryptophan, such as 5-Hydroxy DMT, 5-methoxy DMT, 5-MeO-MIPT, etc, are all very potent drugs. The 5-substituent makes the drug more potent and much speedier, for some resulting in a more “clear headed” high with fewer visuals (especially at lower doses). 5-methoxy (5-MeO) increases the speediness as well as speed of onset, and decreases visuals. All the usual rules for the N,N-dialkyl substituents hold as per usual.
Ring Closed Tryptamines
It may be possible to change the 1 ethylamine group (aka “terminal amine) to a ring closed structure by adding a substituent onto the terminal amine that would be able to link back up to the other two closed rings, transforming it into something that resembles the LSD structure with its 4 closed rings
Conclusion
These are the basic variations on the tryptamine structure that result in psychedelic substances. There are many more variations that are possible and I don’t believe that we have even produced, let alone studied, all the tryptamines that we expect to be psychoactive, or to have psychedelic activity, and thus we are probably nowhere near close to having discovered all their is about these compounds.
What I look for in a tryptamine is a 4-hydroxy or 4-acetoxy substitution, with a N.N-methylisopropyl substituted (or dimethyl or diisopropyl) onto the terminal amine. A 5-methoxy group might also be interesting for its stimulating effects, although I have little knowledge of this substituent yet (that should change soon)
N,N-Dimethoxytryptamine, DMTmost common tryptamine found in Ayahuasca mixtures, and some South American snuff
4-Acetoxy-N,N-Dimethyltryptamine - O-Acetyl-Psilocin, Psilacetin
5-Methoxy-N,N-Methoxyisopropyltryptamine - 5 MeO-MIPT -
Moxy
Psychedelia (in progress)
Psychedelic Tryptamines
Serotonergic Projections from the Raphe Nuclei
From Chemicals to Psychology
What is Psychopharmacology
Specific Psychopharmaceuticals
Psychedelic Tryptamines
