Tryptamine, N,N-diethyl-5-methoxy · Indole, 3-[2-(diethylamino)ethyl]-5-methoxy · N,N-Diethyl-5-methoxytryptamine · 3-[2-(Diethylamino)ethyl]-5-methoxyindole
5-Methoxy-N,N-dipropyltryptamine
SYNTHESIS: (from 5-methoxytryptamine) A solution of 0.95 g of free-base 5-methoxytryptamine was dissolved in 10 mL warm IPA and, after returning to room temperature, treated first with 2.8 mL diisopropylethylamine followed by 1.2 mL bromoethane. After 3 days, TLC showed considerable starting material, so there was added an additional 2.8 g of the amine and 1.2 g of the bromide and the room-temperature stirring continued for an additional 3 days. The volatiles were removed under vacuum, and the residue treated with 1.6 g acetic anhydride, and heated on the steam bath for 20 min. The excess anhydride was destroyed by the addition of 3 mL concentrated NH4OH, followed by dilution with 100 mL 0.5 N H2SO4. The aqueous phase was washed with 3×50 mL CH2Cl2, made basic with 6 N NaOH and extracted with 3×25 mL CH2Cl2. The solvent from the pooled extracts was removed under vacuum, and the residue distilled at the KugelRohr. A fraction boiling at 190–200 °C at 0.5 mm/Hg providing 0.45 g of a white oil. This was dissolved in 2.5 mL IPA, acidified with approximately 8 drops of concentrated HCl which produced spontaneous crystallization. There was added, slowly and with good stirring, 20 mL of anhydrous Et2O to yield beautiful white crystals of N,N-diethyl-5-methoxytryptamine hydrochloride (5-MeO-DET), weighing 0.50 g (35%) and with a mp 190–191 °C. IR (in cm-1): 817, 830, 930, 1109, 1185. MS (in m/z): C5H12N+ 86 (100%), C3H8N+ 58 (12%); indolemethylene+ 160 (4%); parent ion 246 (2%).
The pooled extracts of the CH2Cl2 washings of the acidified aqueous phase above gave, upon removal of the solvent under vacuum, a brownish residue that crystallized. Recrystallization of this from MeOH gave 0.44 g of N-ethylmelatonin as a white crystalline solid. IR (in cm-1): 790, 829, 929, 1031, 1068,1108, 1182, 1199. MS (in m/z): 173 (100%); indolemethylene+ 160 (67%); parent ion 260 (14%). This amide proved extremely difficult to hydrolyze.
(from 5-methoxyindole) To a well-stirred solution of 1.5 g 5-methoxyindole in 15 mL anhydrous Et2O there was added, dropwise over the course of 30 min, a solution of 1.4 g oxalyl chloride in 15 mL anhydrous Et2O. Stirring was continued for an additional 15 min during which time there was the separation of 5-methoxyindol-3-ylglyoxyl chloride as a red crystalline solid. This intermediate was removed by filtration and washed with Et2O, and was used directly in the following step. This was added in small dabs to 2.0 g anhydrous diethylamine, cooled and well-stirred. The off-white resulting solids were suspended in 100 mL 1 N HCl, stirred until it was a loose and creamy texture, then filtered and washed with H2O. Recrystallization from acetonitrile gave 2.24 g (80%) 5-methoxy-N,N-diethylindol-3-ylglyoxylamide N,N-diethyl-5-methoxyindol-3-ylglyoxylamide as white solids, with a mp of 158–160 °C.
A solution of 2.1 g 5-methoxy-N,N-diethylindol-3-ylglyoxylamide N,N-diethyl-5-methoxyindol-3-ylglyoxylamide in 35 mL anhydrous THF was added, slowly, to 3.2 g LAH in 60 mL THF which was well-stirred and held at reflux temperature under an inert atmosphere. After the addition was complete, reflux was maintained for an additional 16 h, the reaction mixture cooled, and the excess hydride destroyed by the cautious addition of wet THF. Aqueous 15% NaOH was added cautiously until the solids had a loose white cottage cheese character to them, and the mobile phase tested basic by external damp pH paper. These solids were removed by filtration, washed with first THF and then with MeOH. The filtrate and washings were combined, dried over anhydrous MgSO4, and the solvent removed under vacuum. The residue was distilled yielding a fraction boiling at 190–200 °C at 0.5 mm/Hg that weighed 1.45 g and was a white oil. This was dissolved in 8 mL IPA, acidified with concentrated HCl until it was acidic to external damp pH paper, and diluted with Et2O and stirred until crystallization appeared to be complete. N,N-diethyl-5-methoxytryptamine hydrochloride (5-MeO-DET) was obtained as white crystals, weighing 1.60 g (74%).
DOSAGE: 1–3 mg, orally
DURATION: 3–4 hrs h
QUALITATIVE COMMENTS: (with 2 mg, orally) "My tinnitus is really out there, and there is no way of getting away from it. Light-headed in a funny way—no hypotension, not dizzy—maybe something to do with the inner-ear? It is in the head, I am attentive, and I am not comfortable. Three hours into it I am down, and I have a bit of wine, and I am aware of it. Am I drunk? Was I drunk earlier? I was intoxicated, to be sure.
(with 3 mg, orally) “It hit in a half hour, and the thought that came to mind was the phrase from my days at college, “Boy, I really felt that drink!” I may be sloppy, but let me explore the sexual. Wow. I may be spacey in the head, but my body knows where it is at. The next day was normal. I don’t think I want to do this again.”
(with 3 mg, orally) “Effect felt within 20
mainly light-headedness, almost dizziness. This blocked anything else. Just wanted to stay quiet and hope it would all go away as soon as possible. During the next hour, lying beside husband (who was experiencing the same effect but not minding it as much), I became aware of another dimension behind the dizziness. I could sense enough of it to believe that it would have been interesting to explore, but that there was no way to get through the dizzies, which effectively blocked anything else. At approximately the hour and a half to two-hour point, I felt a faint lessening of the head-fuzzies, and tested it out by walking to the living room. Felt it necessary to walk carefully. Body felt heavy and mood was rather dark, verging on depressed. After that, attempted love-making, which was extraordinarily successful for husband. For myself, there was still a reluctance to let down my guard. My back problems had been bothering me quite a bit, during all of this, and even two Bufferins didn’t help as much as I would have liked. It’s quite obvious that, if it were possible to remove the part of the molecule that causes the dizzies, this would be one of the best drugs for erotic stuff imaginable. And if wishes were horses, etc. Too bad. Would I try this again? And at a higher dosage? No, and No. ”
(10 mgs, smoked with peppermint leaves) “After a few minutes a high feeling with some dizziness, intense heartbeat, trembling, anxiety, restlessness, cold sweating, paleness and weak belly cramps. There were some visions I could not concentrate because of the strong side-effects. I felt sick, went to bed and was very glad when the effects disappeared after about one and a half hour.”
EXTENSIONS AND COMMENTARY: The is one of the most provocative temptresses I have ever encountered in the tryptamine world. It is a case of having a protégé that you absolutely know will be a success if allowed to come to fulfillment, and yet you know that uncontrolled circumstances will prevent that fulfillment.
Here is a simple, easy to make compound that lies in-between the lower homologue, (active at 10+ milligrams by any parenteral route) and (active at 10+ milligrams orally). The most rudimentary logical demands, yea, screams, that 5-MeO-DET should be active at 10+ milligrams, probably also by the oral route. That is the clear potential of this individual. But, at a fraction of this dosage, an unexpected new property is apparent, one that suggests neurotoxicity, and thus will preclude the achievement of that 10 milligram psychedelic potential. There is a light-headedness, a vertigo and intoxication, a warning of fragility, that pretty effectively blocks any exploration into area that might be psychologically virtuous. This is reinforced by a report I had received from a person who had smoked some 10 milligrams of it. His report is in the qualitative comments above. He described it as a “torture psychedelic.”
This is a new and totally unexpected negative activity may well be unique to this particular diethyl material—it certainly was not reported with either of the immediate homologues, the dimethyl or the diisopropyl. And, as an intriguing corollary, could the unexpected new activity property that brought the physical concern also be the thing that brought the terrific erotic enhancement? Are they tied together as a single new component of action? Or might there be two new components of action, the scary vertigo and the friendly sexual?
To me, an obvious bridge to help explain this seeming discontinuity, would be the dipropyl analogue, I made the compound, and explored it up to its active levels. It is an easy compound to make, and has been known in the scientific literature for may years. My quandary was how to present it in this book. Should I make it a recipe in its own rights, giving the detailed synthesis and a formal position as an active tryptamine? But its actions are ambiguous, and not totally positive, making an argument for its inclusion as a footnote in some other, more interesting recipe. It is this latter route that I have chosen, so here is the 5-MeO-DPT story, both chemical and pharmacological, tucked away in the bigger 5-MeO-DET.
CHEMISTRY: To a warm solution of 0.9 g 5-methoxytryptamine in 10 mL isopropanol IPA there was added 2.8 mL diisopropylethylamine and 1.5 mL propyl iodide, and the mixture was heated on the steam bath for 5 h. TLC analysis at this time showed the presence of both the mono- and the dialkylamines, but there was no indication of the presence of unreacted 5-methoxytryptamine or of the quaternary salt. After removal of the volatiles under vacuum, a CH2Cl2 solution of the residue was treated with 1 g acetic anhydride (on the steam bath for 5 min) followed by 2 mL ammonium hydroxide. Extraction of this solution with 1 N H2SO4 proved to be almost worthless, as the extracts after separation, alkalinification with 6 N NaOH, extraction with CH2Cl2 and distillation of the residues following removal of the solvent, provided only a few milligrams of the desired product. The product had remained in the CH2Cl2. The solvent was removed under vacuum, and the residue partitioned between methanol MeOH (containing a small amount of aqueous NaOH) and hexane. The hexane fraction was concentrated under vacuum to provide 0.54 g of an almost colorless oil which was distilled by KugelRohr. A white oil was obtained, boiling at 170–180 °C at 0.04 mm/Hg which weighed 0.49 g. This was dissolved in 2.5 mL isopropanol and neutralized with 8 drops of concentrated HCl. The solution was diluted with 25 mL anhydrous Et2O to provide 5-methoxy-N,N-dipropyltryptamine hydrochloride as a white crystalline salt. This was removed by filtration, washed with Et2O, air dried to constant weight, and weighed 0.54 g. The mp was 193–194 °C. IR (in cm-1): 811, 828, 929, 1079, 1103, 1186. MS (in m/z): C7H16N+ 114 (100%); methoxyindolemethylene+ 160 (13%); parent ion 274 (3%).QUALITATIVE COMMENTS: (with 4.0 mg, orally) “Within the hour there is something and after another hour there is nothing. Happy to go on up.”
(with 6.0 mg, orally) “I am up above background for sure. Maybe to a ++, erotic maybe, and not too much light-headedness. It is comfortable. Completely out before the fourth hour.”
(with 8.4 mg, orally) “Aware in 12 minutes, some head noises at 20 minutes. These noises are reminiscent of the 5-MeO-DET in that they were “bells” which were bad and the underlying “turn-on” which was good. But the “bells” were outweighing the “turn-on.” Let’s ride it out but then, for that matter, what choice is there! At the 25 minute point the turn-on now outweighs the bell noise. But these keep alternating. Pulse 84; no cardiovascular. But for the next half hour, the bells > the turn-on. At three hours, almost baseline, and I eat modestly. I have better things to do with my time.”
There is the irrepressible fascination of this type of research. Could one tinker with the molecule to emphasize one new property and de-emphasize another? Here is the theoretical conundrum stripped of arcane chemical words and put into non-technical symbolism. Give a single letter to a substitution group, increasing as the group increases in size. Here is the code:
| A = hydrogen |
| B = methyl |
| C = ethyl |
| D = propyl |
| E = isopropyl |
| F = butyl |
| G = sec-butyl |
And let’s arrange the 5-methoxylated tryptamines in order of increasing mass, and see if there is a pattern apparent as to the quantity or quality of action.
| A A | anti-radiation, not a psychedelic | ? | |
| A B | unknown activity | ? | |
| B B | positive, psychedelic, out-of-body | 6–20 mg | |
| B E | mixed, complex | 4–6 mg | |
| C C | negative, vertigo, erotic | 2–3 mg | |
| C–C | very negative, amnesia | 0.5–2 mg | |
| D D | neutral, balance, good and bad | 6–10 mg | |
| E E | positive, LSD-like psychedelic | 8–12 mg | |
| F F | known compound, unknown activity | ? | |
| G G | unknown compound | - |
So, I ask, how could C C be modified to eliminate the vertigo component, maintain the erotic component, perhaps even maintain the psychedelic component, and certainly maintain the orally active property. Clearly, tying them together in the form of a pyrrolidine ring didn’t do it. Only one of these listed 5-methoxy of known activity is asymmetric, the methyl isopropyl analogue. It is probably through this device of mixing and comparing, that our answer will be found. Some guide might come from the 5-hydrogen counterparts, more of which have been explored in man. The variations with a constant isopropyl group have been organized in the recipe for . Here is the rest of the story.
| B C | positive, psychedelic | 80–100 mg | |
| B D | unknown | >50 mg | |
| B E | mixed, complex | 10–25 mg | |
| B F | mixed | 250–400 mg | |
| B G | unknown | ? | |
| C E | mixed | 24–40 mg |
My hope is that getting leads from the second list (no substituent at the indolic 5-position) could help guide the choice of asymmetric substituents for the first list (a methoxy group at the 5-position) that would lead to an expected increase in potency but to an unexpected change in quality of action.
Kierkegaard probably summed it up, best. “Life is not a problem to be solved, it is a mystery to be lived.” That’s chemistry, friends; that’s life!
21 May 2016 · · Isomer Design
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.”
Copyright notice
The copyright for Book I of TiHKAL has been reserved in all forms and it may not be distributed. Book II of TiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
Ordering information
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.
Transform Press,Box 13675
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