Go to TiHKAL • info home
Browse the short index of TiHKAL tryptamines. Read book II of TiHKAL
Search for tryptamines and related structures Beyond TiHKAL—Selected writings by Sasha and others. Explore tryptamine structures and analogues
The alkaloids of the peyote cactus. How TiHKAL • info differs from the printed version
Go to PiHKAL • info home
Book II of TiHKAL: The Continuation, by Alexander & Ann Shulgin #53: T
#53 T: Tryptamine; Indole, 3-(2-aminoethyl); 3-(2-Aminoethyl)indole

#53 T SYNTHESIS: (from indole) To a cold solution of approximately 25% aqueous dimethylamine (most easily made by dissolving 20 g dimethylamine hydrochloride in 20 g cold 50% NaOH) there was added 30 mL acetic acid followed by 17.2 g 37% HCHO. This mixture was added to 23.4 g indole crystals, and the combination was allowed to stir overnight. This reaction was then quenched by pouring into 40 g KOH in 300 mL H2O. A yellowish gum settled out and slowly solidified and was washed with 2×100 mL H2O. The yellow solids were dissolved in 100 mL CH2Cl2 and extracted with 2×200 mL 1 N H2SO4, the extracts pooled, and washed with an additional 50 mL CH2Cl2. The nearly colorless aqueous phase was made basic with 25% NaOH, and extracted with 3×75 mL CH2Cl2. Removal of the solvent under vacuum yielded a white solid residue which, on recrystallization from acetone, yielded 11.0 g 3-(dimethylaminomethyl)indole (gramine) as a loose white crystalline product with a mp 131–132 °C. IR (in cm-1): 749, 832, 868, 1000, 1040, 1119 and 1174. MS (in m/z): indolemethylene+ 130 (100%); parent ion 174 (21%). The yield is very dependent on the amount of H2O present and the temperature of the reaction. Here, with H2O intentionally introduced as a simplification, there was the generation of some 1,3-bis-(dimethylaminomethyl)indole (MS (in m/z): C3H8N+ 58 (100%); indolemethylene+ 129 (7%); parent ion 231 (3%)), considerable yellow gum not soluble in either CH2Cl2 or H2O, and considerable recoverable indole. This yield (here, 32%) has been reported to approach quantitative with the use of anhydrous dimethylamine and only acetic acid as a solvent.

To a solution of 15 g NaCN in 30 mL H2O there was added a solution of 10.0 g 3-(dimethylaminomethyl)indole in 100 mL EtOH, and the reaction held at reflux for 80 h. The solvent was removed under vacuum and the semi-solid residue dissolved in CH2Cl2 and washed several times with dilute HCl (caution, HCN evolved). After removal of the solvent, the residue was distilled at the KugelRohr to give 7.1 g (yield of 79%) of indole-3-acetonitrile (bp 140–150 °C at 0.1 mm/Hg) as a white oil. IR (in cm-1): 751, 824, 930, 1017, 1070, 1103; CN at 2265, NH at 3420. MS (in m/z): parent ions 155, 156 (100%, 66%); indolemethylene+ 130 (56%). The product is a crystalline solid (mp 35–37 °C) but was used in the following reaction without further purification. From the distillation pot, the byproduct indole-3-acetamide could be obtained, with a mp 150–151 °C from aqueous EtOH.

A solution of 6.0 g indole-3-acetonitrile in 15 mL anhydrous THF was added, dropwise, to 160 mL of a 1 M solution of LAH in THF, stirred and held under reflux conditions. After an additional 8 h reflux, the reaction was cooled, and the excess hydride and reaction complex were decomposed by the careful addition of wet THF until the evolution of hydrogen ceased, then 25 mL 5% aqueous NaOH was added, followed by sufficient H2O to leave the inorganic solids with a filterable texture (about 15 mL additional). These solids were removed by filtration, the filter cake washed with THF, the filtrate and washings combined, and the solvent removed under vacuum. The solid residue was recrystallized from CH3CN to provide 5.3 g (86%) tryptamine as a cream colored crystal with a mp 112–114 °C. IR (in cm-1): 751, 811, 882, 941, 1014, 1112 and 1128.

This synthetic scheme is probably not needed by the chemist. There are many commercial sources of indole and, for that matter, for gramine, for indoleacetonitrile, and for tryptamine itself. In general the commercial price goes up modestly, with each sequential material named in this reaction scheme. Tryptamine itself, as the hydrochloride salt, is disproportionately expensive and, in most reactions, must be converted back to the free base before use.

DOSAGE: 250 mg, intravenously

DURATION: Very short

COMMENTS: (with up to 10 mg, intravenously) “There were no changes in blood pressure or self-rating scores.”

(with 250 mg, intravenously) “Tryptamine was infused intravenously over a period of up to 7.5 minutes. Physical changes included an increases in blood pressure, in the amplitude of the patellar reflex, and in pupillary diameter. The subjective changes are not unlike those seen with small doses of LSD. A point-by-point comparison between the tryptamine and LSD syndromes reveals a close similarity which is consistent with the hypothesis that tryptamine and LSD have a common mode of action.”

EXTENSIONS AND COMMENTARY: This quotation is from a paper by Martin and Sloan, published almost thirty years ago, that stands as our only measure of the human response to tryptamine. The first of the two reports in the comments took place 5 years earlier, with depressed patients and at very low levels of drug administration. It had already been established in rat and dog studies that tryptamine was known to enter the brain but, due to rapid metabolism, had only a short duration of central activity. Hence, the researchers in both these studies chose to employ an intravenous route of administration. There are a number of valuable points to be made in this latter report describing the 250 mg study.

Clearly, the model drug in vogue at that time for central action was LSD, and all researcher felt that comparisons should be made to it, as sort of a gold standard. It was acknowledged that the setting in which an experiment took place could influence the outcome. Many studies with LSD were conducted in an environment that was quite different (in private living rooms, with good music and friendly faces) than these tryptamine experiments conducted in a clinical ward of the Lexington Addiction Center, with automatic patellar reflex hammer strokes and polygraphic pupillary diameter measurements, conducted in what was in fact a narcotics prison.

Most instructive was the statement that the tryptamine syndrome was similar to the LSD syndrome. This equation has been broadly quoted, but it is valuable to read, first hand, the explicit observations of central activity that supported this conclusion. These are quoted here:

“Shortly after the onset of the infusions, three of the patients became aware of the experimental setting and complained of a heaviness, tiredness or numbness of the limbs which subsequently became generalized to other parts of the body. With continued infusion, a variety of other visceral symptoms and signs emerged which have been previously described following administration of LSD and mescaline, including nausea, vomiting, dizziness, sweating, acute or dulled hearing, metallic taste, and a heaviness of body. Further, in 2 of the 4 subjects, there were visual changes (subsequently described as a heaviness behind the eyes, a clouding of vision, and lines or cobwebs).”

The tryptamine experience sounds pretty heavy, and it is almost as if every negative LSD or mescaline property was exhumed and displayed, to justify tryptamine as being similar to this widely accepted psychedelic drug.

Why is tryptamine of any interest at all? Just as the simple compound phenethylamine was the nucleus for all of the potential psychedelic compounds in PiHKAL, so tryptamine play plays a similar role as the nucleus of all drugs discussed in this volume. These are the structural basic-skeleton archetypes of these two corresponding classes of psychedelic drugs. Both are widely scattered throughout the plant Kingdom kingdom, and they are both normal components of the human animal. They both have amino acid origins, phenylalanine for phenethylamine and tryptophan for tryptamine, and these amino acids are extremely important factors in human biochemistry. And they, each in turn, can only provoke pharmacological effects when administered parenterally at very high levels.

Tryptophan, the metabolic precursor to tryptamine, is itself a centrally active amino acid. There is a complex, and little appreciated story associated with it as to its human psychopharmacology. Although tryptamine is only active parentally, tryptophan is active orally and is directly converted to tryptamine, the two compounds must be considered in concert. What is the action of tryptophan, taken orally? Here are some quotations from the published literature, mostly with the voice of the giver, not the taker, with some copy taken from health-food store fliers of a decade ago.

COMMENTS: (with 2 g, orally) “I administered two grams to 7 normal subjects, and five 5 of them became drowsy after 1–2 hours.”

(with 2 g, orally) “The amino acid tryptophan is a safe, non-addictive sleeping aid which works because it is made into serotonin in the brain. Serotonin is the neurotransmitter which initiates sleep. Tryptophan is found in milk and bananas and can sometimes be purchased in pill form. Two grams of tryptophan just before bed is very helpful in getting to sleep. For best results take it on an empty stomach. Although milk contains tryptophan, the pure amino acid is more effective.”

(with 5 g, orally) “I took five grams orally several times over a period of days (to study urinary metabolites) and I did not expect any psychological effects. Within an hour, there was a slight dizziness, a feeling of light-headedness and some euphoria which was comparable to whiskey.”

(with 6 g, orally) “We gave six grams tryptophan orally to seven subjects. All became listless and yawned frequently, and five of them slept between the periods of testing. Three were unable to remain awake for more than a few minutes. All were easily aroused however, and then felt euphoric and were unusually voluble and overactive. One showed marked social disinhibition in his behavior. Two were clumsy in turning and tandem walking. One had a frontal headache and another was dizzy without vertigo.”

(with 10 g, orally) “We gave our sixteen normal subjects 10 g d,l-tryptophan d,L-tryptophan orally. All experienced symptoms such as changes in perception (lightheadedness and dizziness) and changes in mood, mainly euphoria. None of the thirty four chronic alcoholic subjects noted any symptoms at this dosage level.”

(with 15 g, orally, with 150 mg iproniazid) “This was a daily treatment given to schizophrenic patients, tryptophan along with an antidepressant which is a monoamine oxidase inhibitor. Most showed marked changes such as an elevation in mood, an increased involvement with other people in their ward, and an increased extrovertism. A separate study of this combination with the addition of the amino acid l-methionine L-methionine produced in about half of these patients a toxic or delirioid state.”

CONTINUING COMMENTARY: Look at this fabulous story that unfolded some twenty years ago. It is completely coherent, and it is totally exciting. Let me try to distill the human information given above, into a logical flow. Tryptophan, a natural and nutritionally essential amino-acid, is a centrally active intoxicant and sleep-provider in man. It is converted metabolically to tryptamine which is a little bit psychedelic. When administered with methionine (another amino-acid known to methylate things) it produces methylated tryptamines, the two best studied being N-methyltryptamine (NMT) and N,N-dimethyltryptamine (DMT). The effects that result are hard to categorize, reflecting the diagnostic status of the patient. But something happens. In short, tryptophan, alone or in combination with MAO inhibitors or methyl donors, is a fabulous tool for exploring brain function. And it was an easily available research tool, openly explored by many private individuals. It was meeting inspiring a broad curiosity as to meeting a large number of human inadequacies.

Then, an incident occurred in 1989, at the Showa Denko company in Japan, where a change in the manufacturing procedure produced an impure product. The impurity led directly to a health problem, a condition with a flu-like syndrome called Eosinophilia-Myalgia Syndrome (EMS) which cause some 1500 incidents in the United States, including 38 deaths. The FDA quite rightly removed tryptophan from the market on the 17th of November, 1989 and banned its distribution. The source of the health problem was quite quickly identified, and the production operation was changed back to the original process, and the tryptophan product was again available free of any toxic impurity. This freedom from any impurity was acknowledged by the FDA, but they transferred the toxic aspect of the substance from the impurity contained within it (now no longer present) to the substance itself. The implied declaration was that tryptophan was intrinsically toxic.

The sale of tryptophan as dietary supplements for man is now illegal. Dietary supplements to animal stock feed is OK okay. Tryptophan is available to hospitals for use in critical situations. Tryptophan is available as a prescription drug. But it is not available in the health food stores and so cannot be explored by the lay researcher. The world of inquiring into the action on normals, schizophrenics, alcoholics, people who are overweight, people who are depressed, is denied both to the private individual and to the clinical researcher. There are commercially available drugs, all approved, that can play the same role. Within four days of the announced ban of tryptophan (after the problem had been resolved and corrected) a broad promotion of Prozac (an antidepressant similar in action to Tryptophan) appeared in Newsweek (March 26, 1990). Prozac is still widely promoted. Tryptophan is still not available to the private individual. Both can play the role of being an effective sedative.

A quotation from the FDA Dietary Supplement Task Force Report, page 2, June 15, 1993, deserves careful reading.

“The [FDA] Task Force considered various issues in its deliberations, including … what steps are necessary to ensure that the existence of dietary supplements on the market does not act as a disincentive for drug development.”

What are dietary supplements? How might they get in the way of pharmaceutical industry creations? Where is the line to be drawn between nature and big business? What plants are there that might serve as health adjuncts? I truly think that we are being had by the powers that be, who are authorized to control our access to medicines. Today we cannot eat ABC because it contains an outlawed drug. Tomorrow we cannot eat DEF because it is suspected of containing an outlawed drug. The day after tomorrow, we cannot eat GHI because it has not been shown to be free of outlawed drugs. And yet, everything in the drug store had its origins somewhere in a botanist’s observation or in a chemist’s mistake. Where does this oppression stop? When do we say, hold, enough?

We must be free to eat this plant, and smell that flower, as we choose to. To deny us this right, is to deny us a simple, and basic freedom that is our Constitutional identity heritage. If I want to continue to eat bananas and drink milk, I will do so, and get off of my back. If I want to consume tryptophan because I feel it brings me closer to God and Jesus, or makes me sleep better, I will consume tryptophan. You, the empowered authority, will not tell me not to. As was so eloquently expressed in Leonard Bernstein’s West Side Story, when the hero group of heroes came up against the authority group of authorities, they said, “Hey, Officer Cronsky, fuck you. Krupke, krup you!

There are a pile of pharmacological details that should be collected and disposed of. For example, l-tryptophan L-tryptophan is the natural and normal amino acid and yet it is more toxic than the unnatural d-isomer. The rat data would suggest that it might be a problem at a something over a 100 gram dose, although I know no one who has nibbled that high. In fact, l-tryptophan L-tryptophan is the most toxic (in rats at least) of all the natural dietary amino acids. Interesting. So But, so what? And there is a botanical side to all of this. Gramine is a synthetic precursor of tryptamine, and yet it has been reported here and there as a natural plant component. The same is true for indole-3-ethanol. Yet, both of these can serve you in the laboratory for the synthesis of tryptamine and, of course, of DMT. The plant world seems to be fully aware of these same processes.

A final comment to connect man and plant. The primary animal metabolite of both tryptamine and of DMT is the corresponding indoleacetic acid which is itself a potent plant hormone. This just happens to be one of the most thoroughly studied plant growth hormones, and has been isolated from a number of natural sources. Less well studied is the reduction product of the intermediate aldehyde, by the action of monoamine oxidase, to the corresponding alcohol, indole-3-ethanol or tryptophol. This rather rare plant stimulant has recently been found in cucumber seedlings, but has also been shown to be present in trace amounts (along with the hormone indoleacetic acid, MMT and DMT) in at least one Ayahuasca component, the Illinois Bundleflower legume, Desmanthus illinoesis. Another circle has closed upon itself in an interesting way.

Page updated 30 March 2012 · This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License ·

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 match the printed version—I’ve found over 300 inconsistencies. Text has been inserted, deleted, or changed at various points. Perhaps the Erowid version was created from an earlier (or later) draft? In several places the Erowid version is plainly wrong; elsewhere it’s a tougher call. I don’t claim to have found every discrepancy; in those cases I have found, both the Erowid and print versions are given and marked as such. I would be grateful if any sharp-eyed readers would report any I have missed.

As with PiHKAL • info, I’ve again attempted to reproduce the typographic style of the printed edition. And again, I’ve also made minor changes to some chemical names in line with current nomenclature practice, and in the hope of aligning with more readers’ searches. Typically the change is little more than expanding a prefix and setting it in italics. The errata and changes page has further details.

Cautionary Note

“I would like to take a moment to reiterate that 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

Copyright Notice

The Copyright for Part 1 of TiHKAL has been reserved in all forms and it may not be distributed. Part 2 of TiHKAL may be distributed for non-commerical reproduction provided that the introductory material, 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.

Although 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
Berkeley, CA 94701

510 · 934 · 4930 (voice)
510 · 934 · 5999 (fax)