Harman, 6-methoxy-1,2,3,4-tetrahydro · β-Carboline, 6-methoxy-1-methyl-1,2,3,4-tetrahydro · 6-Methoxy-1,2,3,4-tetrahydroharman · 10-Methoxy-3,4,5,6-tetrahydroharman · 6-Methoxy-1-methyl-1,2,3,4-tetrahydro-β-carboline · 1-Methylpinoline · Adrenoglomerulotropin · Aldosterone-stimulating hormone · McIsaac’s compound
#44 6-MeO-THH SYNTHESIS: (from ): To a gently refluxing solution of 1.6 g melatonin in 120 mL dry xylene there was added in small portions 14 g P2O5 over the course of 45 min. The solvent was removed under vacuum, and the residue treated with H2O, then made basic with dilute NaOH, and extracted with Et2O. Removal of the solvent from the pooled extracts and recrystallization of the residue from EtOH gave 1.0 g 6-methoxyharmalan with a mp 205–207 °C. High vacuum sublimation gave a product with a mp 208–209 °C. IR (in cm-1): 801, 824, 849, 990, 1031, 1076, 1182. MS (in m/z): Parent ion -1, parent ion 213, 214 (100%, 83%); 170 (22%); 195 (19%). This base can be dehydrogenated by heating 0.7 g with 3 g of Pd-black in a sealed tube for 30 min at 200 °C. The reaction mixture was treated with hot alcohol, filtered, and the filtrate stripped of solvent under vacuum. This gave 0.4 g 6-methoxyharman with a mp 266–267 °C from aqueous EtOH. The mp after recrystallization from MeOH is reported to be 273–274 °C. IR (in cm-1): 621, 698, 835, 1028, 1075, 1184. MS (in m/z): 197 (100%); parent ion 212 (66%); 169 (37%).
To a solution of 0.10 g 6-methoxyharmalan in 5 mL dilute HCl there was added 10 mg PtO2 followed by the dropwise addition of 40 mg NaBH4 dissolved in 1 mL of H2O. The solids were removed by filtration through paper, and the cream-colored filtrate made basic with 5% NaOH and extracted with 4×20 mL portions of CH2Cl2. The extracts were pooled, the solvent removed under vacuum, and the solid residue recrystallized from MeOH to give, after air drying to constant weight, 75 mg of free base 6-methoxytetrahydroharman (6-MeO-THH) as a white solid. IR (in cm-1): 797, 832, 975, 1112, 1121, 1148. MS (in m/z): 201 (100%); 186 (43%); parent ion 216 (38%); 172 (21%); 144 (16%).
(from 5-methoxytryptamine) A solution of 1.00 g 5-methoxytryptamine in 25 mL H2O was brought to a pH of 4 with 0.1 M HCl and put in a nitrogen placed under an N2 atmosphere. There was then added a solution of 1.5 g acetaldehyde in 15 mL of 85% aqueous EtOH. The solution was stirred for 2 days at room temperature, and then made basic and held at 0 °C allowing crystallization. There was thus obtained 175 mg (19%) of 6-methoxy-tetrahydroharman 6-methoxytetrahydroharman (6-MeO-THH) as a white solid, with a mp 160–161 °C. The literature also reports a mp of 224–226 °C.
EXTENSIONS AND COMMENTARY: I have decided to completely eliminate the dosage, duration and qualitative comments for this compound, and all related analogues. The reason is painfully obvious—virtually nothing is known about their psychopharmacology. Despite their enormous potential for someday being understood as possible intermediates in brain chemistry, they remain almost unexplored. I was working closely with Dr. C. Naranjo in the middle ’60’s in this area, on a study we were considering co-authoring, to be entitled, “Hallucinogenic Properties of a Pineal Metabolite, 6-Methoxytetrahydroharman.” This was recorded in the Ethnopharmacologic Search for Psychoactive Drugs book of Daniel Efron, as being in Science, in press. But, the paper was never in press as it had never been submitted for publication, as it had never been written. All of this for the very simple reason that the research for it was never completed. It had just been started. Claudio had explored both 6-methoxy-tetrahydroharman and the corresponding in the 100–150 milligram area, and was finding some activity. I was running parallel studies and had gotten up to about 100 milligrams and had not found anything. We both saw this as being a rich and promising virgin field for exploring human pharmacology. It still is. Rich and promising. It still is rich and promising. And still virgin. And it still is virgin.
Before the any particulars, some rather broad generals about nomenclature. This world of carbolines is a total bear as to the assignment of chemical names, so this is a logical place to talk about it. Many terms will be encountered. Some are totally trivial such as a specific compound that has been given a name from the binomial of the plant where it had been discovered, as in from Leptactinia densiflora. Some are based on the completely general parent ring system itself, beta-carboline. Many compounds have many synonyms, and the carboline appendix in the back of this book would be a good place to save these names as you find them. For me, I look for middle territory. I look for two clues. The first is a sound that catches my attention immediately, the prefix, “harm-.” This demands that there is a methyl group in the molecule and that it is at the 1-position. The second clue is the vowel that follows the harm-. It will usually be an “a” or an “i” or occasionally and “o.” The harma- things have nothing on the aromatic ring, and the harmi- things have a 7-methoxy group there, and the harmo- things are usually phenolic, with an oxygen attachment there. And the numbering systems can be totally off the wall.
Let me try organize the “harm” chaos first, always with that methyl group at the C-1 position of the carboline ring. And the The second collection has a hydrogen atom there.
indole sub. aromatic (H0) dihydro (H2) tetrahydro (H4)
  1.  each has its own recipe
  2.  included in this recipe
with a 1-methyl substituent
Ar-H 2 (THH)2
Ar-6-OH 2
Ar-6-OMe 2 2
Ar-7-OMe 1 1 1
with a 1-hydrogen substituent
Ar-H (tryptoline)2
Ar-6-OH 6-Ho-βC
Ar-6-OMe 6-MeO-DHβC
Ar-7-OH 7-HO-DHβC
Some minor stumbling blocks remain in this system. βC (β-carboline) has been called nor-harman, since it is harman without the methyl group. This is incorrect in theory in that the prefix “nor” implies that the lost group comes from a nitrogen. Incorrect, but common. Many additional synonyms and botanical locations are given in the carboline appendix. And throughout this discussion, I will totally ignore the chemically correct way of naming beta-carboline, which is 9H-pyrid-[3,4-b]-indole 9H-pyrido[3,4-b]indole.
A brief comment on the numbering systems that can be found. The procedure used here and in the appendix starts counting at the carbon atom of the pyridine ring that is closest to the indole nitrogen. The pyridine nitrogen atom becomes two, and on around hitting every substitutable atom ending on the indole nitrogen as the 9-position. However, as usually in the older literature but still seen sometimes today, the indole nitrogen is the 1-position (as it still is when a structure is seen as an indole) and then every atom, substitutable or not, is numbered sequentially. This brings the 7-substitution identifier of (which is the indolic 6-position) up to the number 11. This makes harmine 3-methyl-11-methoxy-β-carboline. Some years ago the general term “tryptolines” was introduced to embrace the family of compounds with no methyl group on the 1-position. The numbering required that the pyridine nitrogen be called the 1-position effectively maintaining the position numbers of the parent indoles, but it turns out that the original 1-position, now without a number, has to default to the end of the line, to the rather sad 9-position name.
Back to the individual chemical stories. This commentary will cover the scatter of beta-carbolines that might play some major role in the human nervous system, other than the trilogy. Harmine, and all have the oxygen at the 7-position, and mostly have their origins in the botanical world. The six 6-position oxygen can come directly from or hydroxytryptophan, and are found both in plants and animals. Similarly, the hydrogen derivatives (unsubstituted) derive from tryptamine and , again from both plants and animals.
6-Methoxy-tetrahydroharman 6-Methoxytetrahydroharman (6-MeO-THH) is the title chemical of this recipe. This particular β-carboline is a focal points of an ongoing controversy. To put all the cards directly on the table, this compound can in theory be made easily in the body and thus it could be present as a normal component in the brain. It has been synthesized by McIsaac, in Texas, under physiological conditions, with acetaldehyde and 5-methoxytryptamine. And, so the reasoning goes, if it can be made under these conditions in the laboratory, why not in the brain? He was completely convinced that it would be found some day to play an important role in mental health, just as he was convinced that it would prove to be a psychoactive compound. Perhaps it would be the product of some psychological trauma, or maybe be the source of such a trauma. He once told me (at a meeting years ago, over a quiet breakfast) that one of his ambitions was to assay the brains of people who were in all different kinds of mental states at the time of their deaths, and to correlate the carboline levels with that mental state. I asked him if he had personally tasted the material, and apparently he had not.
6-MeO-THβC (6-MeO-THβC, pinoline) is a naturally occurring component of human blood and cerebral spinal fluid. Like 6-MeO-THH, it is readily formed from 5-methoxytryptamine, but with formaldehyde rather than with acetaldehyde. The levels have been found to be similar in schizophrenics and psychiatrically healthy patients, suggesting that it is not a factor in the chemistry of mental illness. It is a natural component of the human pineal gland and is quite effective in binding to sites in human platelets. It has been suggested that the balanced interplay between and pinoline in the manipulation of serotonin levels, might be an explanation of the sleep/dream state. The carbolines just might play an endogenous role in creating dreams, our “asleep” visual tripping.
6-Methoxyharmalan (6-MeO-DHH) was the chemical intermediate in the synthesis given above. Its main claim for attention is that it is the immediate result of the removal of a molecule of water from , which is a major actor in the biochemistry of the pineal gland. It is also a pretty effective monoamineoxidase inhibitor.
Harman is the simplest of the carboline alkaloids, and also one of the most widely distributed throughout the plant world. Many of its common names derive from these sources, such as loturine, aribine and passiflorin. In tasting trials with the alkaloid alone, there are no effect noted at even up to 250 milligrams orally. Rather surprising, even though it has been shown to be a good monoamineoxidase inhibitor, a 250 milligram trial followed in 20 minutes with 35 milligrams of , also had no effects. Clearly harman does not share pharmacological similarities with its methoxylated cousins. Harman is the prototype alkaloid of the β-carboline class and has been found in many plants although not usually a contributor to the action for which they are best known.
It is a component of the bark of the legume Arariba rubra (Sickingia rubra), native to the Bahia state in Brazil, as well as from the bark of Symplocus racemosa. This tree was introduced into Goa in the mid-nineteenth century, and from it has come a drug called Araroba powder (or Goa Powder, Brazil powder, or Ringworm powder). This turn of the century drug of commerce contains the non-nitrogenous anthracene Chrysarobin, isolated commercially from the closely related legume, Andira araroba (Vouacapoua araroba). It has been used in the treatment of ringworm and a number of skin diseases. plays no part in this medical use. I have not been able to pin down just why harman has been given the name Loturine. Some Genus, no doubt, but I don’t know what it is.
It is, however, a recognized component of the extracts of the passion flower Passiflora incarnata, but the much more plentiful inventory of flavinoids present in this marvelously named plant seem to be the agents that are responsible for its sedative properties. Again, is probably not an active contributor to the reported pharmacological action. In fact it has been spotted as a component of cigarette smoke, and here it certainly cannot be a factor that contributes to the virtues of smoking.
Tetrahydroharman (1-methyl-1,2,3,4-tetrahydro-β-carboline) has been the topic of many animal studies, but within the last few years it has demanded attention in an unexpected way. A couple of years ago, there was a rash of medical problems that occurred and that were ascribed to an impurity found in certain supplies of the amino acid tryptophane tryptophan. The chemical twist is that the causal impurity appears to be the product of cyclizing tryptophane tryptophan with acetaldehyde. The product of this reaction is 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (tetrahydroharman-3-carboxylate, . It has been generated in experiment animals which have been fed tryptophane tryptophan, ethanol, and cyanamide, (a drug that by interfering with the normal metabolism of alcohol allows an accumulation of acetaldehyde in the body). The introduction of a new chiral center into an already asymmetric system gives promise of a challenging research problem, involving, in any body fluid assay, an interesting analytical problem. Anyway, this aminoacid amino acid decarboxylates to give tetrahydroharman, which was under some suspicion as being involved. Well, it wasn’t, and the story itself has been discussed in the recipe for . It is a story of politics, not of chemistry. Another 3-carboxylic acid derivative, the totally aromatic material without the 1-methyl group, has been found as a natural material in trace amounts in human urine, in fact the yield was a total of 1.78 milligrams from 1800 liters. This is the of . It is an extraordinarily potent inhibitor of brain benzodiazepine receptors but, surprisingly, totally without any affinity for receptors. The hydrogenated version, , as well as the analogue above () are normal components of both beer and wine, being present at the several ppm level.
Since can come from the union of and acetaldehyde, and since both of these compounds are natural components in the body, it is not surprising that tetrahydroharman is also a natural body factor. And, since ethanol is metabolized by way of acetaldehyde, the body level of tetrahydroharman closely reflects the amount of alcohol that had been consumed. A parallel reaction takes place in the human body between acetaldehyde and the neurotransmitter .
6-Tetrahydroharmol This material, , or 5HMTLN (5-hydroxy-9-methyltryptoline) employing the cute tryptoline nomenclature, also reflects alcohol consumption. The levels are, however, unreasonably high for the amount of free acetaldehyde normally adrift in the sober body and so it is suspected of having an alternate synthetic origin, perhaps involving pyruvate.
Tetrahydroharmol The positional isomer with the hydroxyl group at the 7-position, , is noteworthy for two reasons. A minor one, to let it be known that it, too, as with almost all possible combinations of natural tryptamines and aldehydes and acids looked for with diligence and sufficient sensitivity, has been found in human urine. The more impressive item: The use of the “tryptoline” word. Here is a view of an extreme cul-de-sac that was created by this procedure. This is all taken directly from the mass spectroscopy paper published in 1986. The problems arose from the fact that the methyl group of the / world could not be slipped into the name, as its position had no logical number. And that there was no abbreviation for tryptoline that could be distinguished from tryptamine. Either could be “T.” The paper discussed the hydroxylation metabolism of MTLN (methyltryptoline, in reality ) to give the 6- and 7-hydroxylated derivatives. I would call these, 6-tetrahydroxyharmol and tetrahydroxyharmol. But in this research paper, having been committed to the tryptoline word, these metabolites came out as 5HMTLN and 6HMTLN. The “5” and “6” represent the 6 and 7 positions on the carboline ring. The “H” is the hydroxyl group. The “M” is the methyl group which they do not choose to locate, but in the only offered numbering system, it would be in the 9-position. And, of course, TLN is the abbreviation for tryptoline (MT was spelled methtryptoline in the title). I do believe that 6-H-9-M-TLN is harder to understand than tetrahydroharmol.
6-HO-THβC , in an enzymatic interaction with the methyltetrahydrofolate one-carbon source, gives rise to the beta-carboline analogue, . This happens also to be the plant alkaloid plectomine as well as a metabolite of THβC in the rat. Attempts to make from methyltetrahydrofolate and N-methyltryptamine () gave rise exclusively to the carboline .
THβC (THβC, tryptoline) has also been demonstrated as being formed in the brain by the simple fusion of tryptamine with formaldehyde, from methyltetrahydrofolate, and it is a normal component of human urine. It is the structural icon of the family of tetrahydro-β-carbolines without the methyl group at the 1-position, sometimes called the “tryptolines.” It, and the 2-methyl homologue mentioned just above, are both natural metabolites of . I had the lucky timing to be present at a seminar at the Department of Pharmacology, at the U.C. Medical School in San Francisco, when the crowd from Stanford came up to give the first San Francisco unveiling of the “tryptoline” word. I remember that I was not the only chemist in the audience who groaned at the use of a totally unneeded and artificial name. But these researchers did a lot of work and a lot of publishing, and the term is now pretty well established in the literature. A cautionary note is appropriate here. It is essential, in abbreviating this material as THβC that the “β” be included. Without it, the code “THC” will be assumed immediately to stand for tetrahydrocannabinol, the active component of marijuana.
6 Apr 2020 · ·

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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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.

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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.
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