Tryptamine, α,N-dimethyl · Indole, 3-[2-(methylamino)propyl] · α,N-Dimethyltryptamine · 3-[2-(Methylamino)propyl]indole · Alpha-N
#8 α,N-DMT SYNTHESIS: (from indoleacetone) To a solution of 1.55 g NaOAc in 5 mL acetic anhydride there was added 2.0 g 3-indoleacetic acid and the mixture was heated at 135–140 °C for 18 h. Removal of all volatiles on the rotary evaporator under vacuum produced a pale yellow residue that was the 1-acetylindole-3-acetone. This was dissolved in MeOH to which 0.93 g MeONa was added, and the solution held a reflux several hours. After removal of the solvent under vacuum, the residue was suspended in H2O and extracted with several portions of Et2O. These extracts were pooled, and removal of the solvent under vacuum gave 0.41 g (21%) indole-3-acetone as a white solid, mp 115–117 °C. MS (in m/z): indolemethylene+ 130 (100%); parent ion 173 (16%). IR (in cm-1): 691, 753, 761, 780. 1017, 1110, 1172, and a broad C=O at 1710.
To 1 g shredded aluminum foil there was added a solution of 20 mg HgCl2 in 15 mL H2O. After 15 min the amalgamated aluminum was drained free of the mercury solution, well washed with fresh H2O, and shaken as dry as possible. There was then added, in sequence, a solution of 1.5 g methylamine hydrochloride in 2 mL H2O, 3 mL of 25% NaOH, 5 mL of IPA, and finally 1 g of indol-3-ylacetone in 20 mL IPA. This was stirred for 1 h, then heated briefly on the steam bath. After cooling, the reaction mixture was filtered and the solids washed with MeOH, the washing and filtrate combined, and stripped of solvent under vacuum. The residue was dissolved in 200 mL H2O, made acidic with HCl, washed with CH2Cl2, treated with aqueous NaOH to a pH of greater than 9 (becomes cloudy), and extracted with 2×50 mL CH2Cl2. Removal of the solvent from the combined extracts gave a light brown oil which distilled at 125–135 °C at 0.4 mm/Hg to give 0.74 g of a viscous oil. This was dissolved in 5 mL IPA, neutralized with concentrated HCl and diluted with anhydrous Et2O to the point of turbidity. After standing, the solids were removed, washed with Et2O and air dried, to yield 0.87 g of α,N-dimethyltryptamine hydrochloride (α,N-DMT) as white crystals. MS (in m/z): C3H8N+ 58 (100%); indolemethylene+ 131–130 (19, 14%); parent ion 188, just above noise level.
Alternately, the indol-3-ylacetone can be catalytically reduced in the presence of methylamine. A solution of 3.3 g indol-3-ylacetone in 100 mL EtOH was hydrogenated over Pd-C catalyst in the presence of an excess of methylamine. After 2 h the catalyst was removed by filtration, the filtrate stripped of solvent under vacuum, the residue dissolved in H2O and made acidic. After washing with Et2O, the aqueous phase was made alkaline, and the solids that formed removed by filtration and recrystallized from a mixture of hexane and THF. The product, α,N-dimethyltryptamine (α,N-DMT), was a tan solid that weighed 2.2 g and had a mp of 93–94 °C. The picrate is brick red from EtOH, and melted at 207–208 °C.
(from ) A solution of 4.4 g alpha-methyltryptamine (α-MT) in 5.5 g acetic anhydride containing 3.1 g HOAc and 2.4 g HCO2H was stirred at room temperature for 18 h. All volatiles were removed under vacuum at a temperature of less than 40 °C which left a syrup as a residue. To this was added 100 mL H2O and extracted with several portions of Et2O which were combined and the solvent removed under vacuum. There remained 4.9 g (95%) of α-methyl-N-formyltryptamine which was used as such in the next step. This was dissolved in 30 mL anhydrous THF and this solution was added to a gently refluxing suspension of 3.7 g LAH in 30 mL THF, under nitrogen, or 16 h. After cooling the excess hydride was destroyed by the careful addition of wet THF followed by sufficient aqueous NaOH to produce a solid that can be easily removed by filtration. After filtration, the filtrate was stripped of solvent under vacuum and the residue (4.3 g) crystallized from benzene/petroleum ether to give 2.5 g (56%) of α,N-dimethyltryptamine (α,N-DMT) as a solid with a mp 90–91 °C. The N-ethyl homologue, made in a similar way from α-methyl-N-acetyltryptamine, had a mp 187–189 °C.
DOSAGE: 50–100 mg
DURATION: 6–8 hrs h
QUALITATIVE COMMENTS: (with 50 mg, orally) “Something was going on, and it was rather strong a couple of hours into it, but there doesn’t seem to be anything particularly psychedelic here. I am wakeful and alert, maybe a little bit starry-eyed as if I were wearing glasses with the wrong prescription. Maybe a little bit light-headed as well. It was several hours before these physical discomforts disappeared.”
(with 75 mg, orally) “Compulsive sneezing, and quite uncomfortable. Urpy. Tried eating some quiche, and couldn’t do it—no appetite at all. Pulse seems to be proper, but it is almost as if I were using speed without any of the stimulant virtues. After about three or four hours I am losing the buzziness property and am pretty much normal in three or for more hours. Still some teeth clench. Sleep OK. I’m not sure that going higher is worth it. Or even repeating it. Why?”
EXTENSIONS AND COMMENTARY: The relationship between (alpha-methyl tryptamine) and this compound, α,N-DMT (α,N-dimethyltryptamine) is exactly analogous to that seen with the counterparts, between (alpha-methylphenethylamine) and (α,N-dimethylphenethylamine). Both the primary and the secondary amine compounds retain activity. In the camp, both compounds are dramatic stimulants showing a complete spectrum of sympathomimetic properties including cardiovascular excitement, loss of appetite, and sleeplessness. Here, the tryptamine counterparts are similar to one another, but it is not as clear that they are stimulants. In animal studies, they have been compared with each other and with . Except of the speed of onset, both tryptamines caused amphetamine-like behavior in activity cages, but required some 10 times the dosage of . In man there are some suggestion of this, the loss of appetite, the buzzy lightheadedness, and the absence of any of the usual suggestions of psychedelic action.
I mentioned an appealing hypothesis in the commentary on , and it is applicable here. Both of these materials, α-MT and α,N-DMT, are effective monoamine oxidase inhibitors. Both of these materials show some of the syndrome that has been described for the monoamineoxidase inhibitors of the beta-carboline family. It would be interesting to design and conduct a study into the role that either of these might play in promoting the oral activity of the materials of ayahuasca that are deaminated and thus deactivated when taken alone. This entire argument could and should embrace the methoxylated counterpart, . I am not aware of any studied that have been made as to its deaminase enzymatic effectiveness, but it too fulfills that nausea, discomfort, un-psychedelic pattern shown here. The expected increase in potency due to the 5-methoxyl group is proper, making it a more potent compound than either of these two. Let’s put it into the study as well.
In all of these cases, the adding of an additional methyl group to the nitrogen atom makes a tertiary amine. In the analogy, one gets . This compound appeared in a couple of clandestine laboratories a few years ago, as a result of the cooks substituting for the customary precursor, . Although animal studies on showed it to have little if any stimulant properties, the authorities reasoned that since it had appeared in an illicit context (potentially being peddled as a street drug) it had a real abuse potential. And since it had no recognized medical utility, it’s obvious resting spot was in Schedule I of the Controlled Substances Act. And there it was indeed placed.
The application of this structural modification to the tryptamine area, gives α,N,N-trimethyltryptamine (). The tertiary amine in the , , showed a loss in its stimulant nature. Here, the adding of that additional methyl group gives a tertiary amine that has the skeleton of . This base has been reported as having been made by either of two different routes, both starting with indole. Reaction with propyleneoxide gave the 3-indolyl-2-propanol which was treated first with PBr3 followed by dimethylamine. Or, reaction with chloropropionyl chloride gave a 1,3-bis intermediate which was converted to the amino ketone 3-(2-dimethylaminopropionyl)indole with dimethylamine. This was reduced to the same product, α,N,N-TMT, with LAH. The bimaleate salt had a mp of 139–140 °C.
Another parallel exists between the world and the tryptamine world. Rather than adding a second methyl group to the terminal nitrogen, simply keep the one methyl group that is there and lengthen it by another carbon atom. Make the methyl into an ethyl. With the / prototype, this extension provided the homologue and by further extension, , , N-etc. amphetamines. The same manipulation, again in the world where there is a 3,4-methylenedioxy substitution on the aromatic ring, one gets the , , , series of compounds. The exact same world exists with the tryptamines. Lengthening the N-methyl group of α,N-DMT leads to compounds that are known and potentially active in man, but which have not yet been explored. As discussed under , the presence of two different alkyl groups on a tryptamine are best named for those two groups, with their locations given as numbers or letters as prefixes in front of the initialed code. But here the convention becomes hopelessly ambiguous. What is to be done if one of the prefixes belongs to one group, and the other to the other? One has to break them up, of course. But then something else like α-M-N-ET becomes a nightmare to be properly located in the long index. Let’s compromise with where the M is belongs to the α, but the E (ethyl) is on the T (tryptamine) nitrogen atom where it belongs. So, the N-ethyl compound (alpha-methyl-N-ethyltryptamine) becomes α-MET, which comes from and it forms readily through the reductive alkylation of indol-3-ylacetone with ethylamine (HCl salt, mp 187–189 °C, picrate mp 203–205 °C), and the N-isopropyl analog (alpha-methyl-N-isopropyltryptamine) becomes comes and it results from the reductive alkylation of indol-3-ylacetone with isopropylamine (HCl salt, mp 229–230 °C, picrate mp 219–220 °C). Their pharmacology in animals is not exciting, but they are untried in man. Well, maybe they are untried. An early patent (1962) that gives the synthesis for both the N-methyl and the N-ethyl compounds (α,N-DMT and α-MET) and claims that they both have psychostimulant properties.
And, as a final note, be careful. The code TMT has two meanings. In the area it identifies the analog, (or trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine). This is [discussed in] , page 607 of PiHKAL, and check there for further detail details. Here, entries of multiply methylated tryptamines (with the one exception of DMT will be preceded with the specific locations of the methyl groups. Those prefixes such as numbers of Greek letters. Here, entries of trimethylated tryptamines will be preceded with the specific locations of the methyl groups prefixes with numbers, Greek letters, and/or N for nitrogen.
13 May 2016 · Creative Commons BY-NC-SA ·

About TiHKAL · info

This version of Book II of TiHKAL is based on the Erowid online version created by Bo Lawler with the help of Erowid, from content generously provided in electronic format by the Authors.
The Erowid online version does not always align precisely with the printed version. Text appears to have been inserted, deleted, or changed at various points. Where the two are seen to diverge both the Erowid and print versions are given. Sharp-eyed readers are encouraged to report novel discrepancies.
As with PiHKAL, I’ve again attempted to reproduce the typographic style of the printed edition. I’ve again made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.

Cautionary note

“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.
“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
Alexander T. Shulgin

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TiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of tryptamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of TiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
TiHKAL (ISBN 0-9630096-9-9) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.
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