rational exploration of the underground

The indole ring of tryptamine provides a number of possible locations for functional groups to be substituted. Addition of a hydroxy group at the 4-position produces a large number of active psychedelic compounds including some true classics.

4-hydroxylation of alpha substituted tryptamines such as AMT has been conducted but further exploration has been limited due to potential toxic effects.

The 4-hydroxy analogue of α-MT has been looked at in human subjects. It is reported to be markedly visual in its effects, with some subjects reporting dizziness and a depressed feeling. There were, however, several toxic signs at doses of 15 to 20 milligrams orally, including abdominal pain, tachycardia, increased blood pressure and, with several people, headache and diarrhea.

-Alexander Shulgin

4-hydroxylation of the n-alkylated tryptamines is more fruitful. For instance, 4-hydroxylation of DMT (dimethyltryptamine) produces the classic psilocin (4-HO-DMT, 4-hydroxy-dimethyltryptamine). These 4-hydroxy n-alkyl tryptamines are similar in general psychedelic character, moderately potent (active at 10-25 mg) and of medium duration (2-6 hours).

Other functional groups can be substituted at the 4-position which are converted to 4-HO tryptamines in the human body. Psilocybin (4-PO-DMT, 4-phosphoryloxy-dimethyltryptamine) contained in psychedelic mushrooms is water soluble and too polar to cross the blood-brain barrier. After consumption phosphatase enzymes rapidly break apart the phosphoryloxy group producing the active psilocin (4-HO-DMT, 4-hydroxy-dimethyltryptamine).

The phosphoryl group in psilocybin that is cleaved off by enzymes is known as an ester, and other esters can be substituted that react in similar ways once consumed by man.

O-acetylpsilocin (4-AcO-DMT, 4-acetoxy-dimethyltryptamine) can be thought of as psilocybin with an acetoxy group instead of a phosphoryloxy group. Like psilocybin, it is rapidly converted to 4-HO-DMT in the body. This produces a compound with a similar subjective experience to that of psilocybin.

4-HO tryptamines can therefore have a 4-AcO pair with very similar effects. The 4-AcO partner tends to be slightly less potent, have a longer duration, and be subjectively “smoother” than the 4-HO counterpart. It is a matter of debate whether this is simply the result of varying rates of administration due to metabolic conversion, or if 4-AcO tryptamines are active in their own right.

Shulgin, A. #48 AMT. Tryptamines I Have Known and Loved. Transform Press, 1997.

Vito Cozzi, Nicholas. MAPS: Re: Psilocybin and the blood brain barrier. MAPS Forum, April 29 2003.

The amine group of tryptamine possesses a nitrogen with two hydrogens where functional groups can be substituted. Let’s start with the simple case where both of these substitutions are identical. The best known example is dimethyltryptamine, abbreviated as DMT (D for di meaning two, M for the methyl alkyl substitions, and T for the tryptamine backbone). There are other tryptamines like DMT with longer symmetrical alkyl chains which have similar effects and are named in a similar manner.

Some dialkylated tryptamines: dimethyltryptamine (DMT), diethyltryptamine (DET), dipropyltryptamine (DPT), dibutyltryptamine (DBT).

DMT is typically smoked as other consumption routes are ineffective due to MAO degradation, but the longer alkyl chains do not have this issue and are all orally active. There is no theoretical limit to the alkyl chain length, but potency decreases as chain length increases. DBT is the longest simple chain dialkylated tryptamine commonly bioassayed in man.

We can also consider asymmetrical cases where the two substitutions are different. The possible combinations quickly increase in number as the following table up to alkyl chains of three carbons in size illustrates. Asymmetric compounds are referred to by giving initials to both of their substitutions (shortest chain first) and ending with a T to signify the tryptamine backbone.

Linked compounds have a full entry in TiHKAL.

These two rulesets for symmetric and asymmetric substitutions allow us to refer to a huge variety of n-alkylated tryptamines using abbreviations in a simple and consistent manner.

Shulgin, A. #2 DBT. Tryptamines I Have Known and Loved. Transform Press, 1997.

Biological organisms are wondrous little molecular factories, their enzyme catalyzed reactions often accomplishing in a single step what would confound a chemist in a well-stocked laboratory. Researchers have attempted to harness these biosynthetic pathways to create complex molecules not easily synthesized by conventional methods.

Psilocybin is produced via a biosynthetic grid where enzymes act on various closely related intermediate compounds in turn. The enzymes do not appear to be particularly picky about the compounds they modify. For instance, dimethyltryptamine (DMT) is hydroxylated to 4-HO-DMT naturally in psilocybin mushrooms. Other precursor compounds like tryptamine and methyltryptamine are also hydroxlyated to 4-hydroxy-tryptamine and 4-hydroxy-methyltryptamine respectively.

If an entirely new synthetic tryptamine of similar structure was introduced to these mushrooms, would the same enzymes act on it? This could produce a new and unique psychedelic compound where some of the heavy lifting of synthesis is accomplished by the biological expertise of the mushroom itself and not by conventional laboratory chemistry.

Jochen Gartz decided to attempt this by adding diethyltryptamine (DET, a close relative of DMT) to the fruiting body of psilocybe cubensis. He hoped that it would be hydroxylated to 4-HO-DET, or possibly phosphorylated even further to 4-PO-DET. He first colonized a mixture of cow dung and rice grain with psilocybe cubensis, and then injected it with a solution of DET. Within four weeks mushrooms were produced, and five total flushes of mushrooms were obtained.

all values % by weight of dry mushroom

The project was a success, with significant amounts of 4-HO-DET produced. No DET was found in the dried mushrooms. A mass balance was not conducted to determine the efficiency of the conversion and possible losses in the fruiting body itself. The demonstrated non-selectivity of the enzymes in psilocybe cubensis toward other tryptamine derivatives opened to the door to the possibility of producing truly exotic and difficult to synthesize compounds such as 4-HO-5-MeO-DMT.

Despite this little additional data is available on the tryptamine derivatives that are able to be substituted in the fruiting body and the repeatability of the experiment. Some have found little success, noting only a decrease in the size of the mushrooms produced. Other attempts have discovered perhaps a qualitative difference in potency and character of the psychedelic experience, but this has not been substantiated by quantitative measurement.

Biotransformation of tryptamine derivatives in mycelial cultures of Psilocybe. Gartz, J. Journal of Basic Microbiology, Volume 29, Issue 6, Pages 347-352 (1989).

The research chemical market is based on the philosophy of tweaking existing recreational molecular backbones, yet compounds based on LSD appear to be few and far between. There is nothing at all preventing the existence of exotic research chemicals based on the ergoloid backbone, and in fact several are known that have significant recreational potential based on academic studies. The interesting fact is that none of them appear to have hit the market in significant volume. Perhaps this is simply the result of watched precursors and more elaborate synthesis routes than established products, but experimentation by the research chemical market seems rather lackluster based on the reputation of the parent drug and possible potential.

There are some who argue that experimentation of this nature has been ongoing, but has been executed through entirely different distribution channels - namely the LSD black market. Certain blotter prints have been distributed with something that could pass for LSD but seems different to experienced tastes. This particular variant has been described as a sort of neo-LSD that appears more euphoric, more visual, shorter acting, and less “spiritual” with the accompanying decrease in potential for anxiety.

One suspected blotter print is the 1906-2008 Hoffman Oms. This is not a esoteric print with limited circulation. It celebrates the life of Albert Hofmann, who lived from 1906 to 2008 and was the first to synthesize and consume LSD. It is part of a larger recurring blotter art series that is consistently widely distributed and well received, and as such appears to originate from the depths of the notoriously secretive LSD black market.

Sufficient suspicions were raised about the contents of this blotter to instigate a GC/MS test.

Initial evaluation seemed to bear out the hypothesis that these results reflected a novel and interesting compound closely related to LSD, perhaps lysergic acid 2-butyl amide (LSB) or lysergic acid 3-pentyl amide (LSP). These early interpretations of the GC/MS results were challenged however.

sec-LSB gives an almost indistinguishable MS to actual LSD, so I doubt it’s that. It’s not the N-(3-Pentyl) derivative [..] as well[.]

I personally have not a clue what this is — the fragment for d-Lysergic acid diethylamide, LAMPA or sec-LSB is always at 324, yet here we have 326 (the only one that comes to mind is deuterated-LSD which is usually 327). The huge peak at 72 is suspicious and the initial peaks at 44/58 as well (small substituted amines?).

296-208 is usual fragment for N-Et-LSD and a peak adjacent to 209 is present
310-209 characteristic of nor-LSD/nor-iso-LSD

So, you’re missing quite a bunch of the normal peaks but you have what might be degradation products or side impure product present, but it seems pretty inconclusive.

-nuke

Unfortunately it appears that no clear conclusions can be drawn. The blotter cannot be positively identified as LSD, but it also cannot be identified as a closely related compound or even as a completely different psychedelic compound. These blotters were clearly active in man, and displayed a psychedelic character very close to LSD. The major issue is lack of comprehensive test results, as GC/MS analysis is not easily available. Even if these tests are conducted, the data is not typically shared widely. It seems likely that these problems will become more manageable as technology progresses.

It is very likely that closely related compounds to LSD have been synthesized and tested in man. The precursors are available, the skills are out there, and the desire exists. Whether these exotic relatives of the world’s most famous psychedelic remain limited to a select few or have been surreptitiously released on a wider scale to a mostly unaware public remains to be seen.

Bluelight Forum > Focus Forums > Psychedelic Drugs > The Big & Dandy Non-LSD Ergoloids Blotter Thread.

Substitution of sulfur at the 4-position of 2,5-dimethoxyphenethylamine provides a building block for many successful psychedelic compounds, initially explored by Shulgin and named in the format 2C-T-x. Generally, smaller substitutions tend to produce compounds which act as agonists, while larger substitutions are partial agonists or antagonists. The smaller substitutions described in Part I tend to be potent psychedelics, while the larger substitutions discussed here trend toward stimulant effects or are inactive. Determining the precise boundaries of this relationship was a major motivation of Daniel Trachsel who continued Shulgin’s work with the larger substitutions of 2C-T-25 and above.

2C-T-13 (2,5-dimethoxy-4-(β-methoxyethylthio)phenethylamine) Active in doses from 25 to 40 mg, it produces a experience 6 to 8 hours in length. There is a focus on closed eye visual effects, with only slight visual distortions present if the eyes are open.

2C-T-14 (2,5-dimethoxy-4-(2-methylthioethylthio)phenethylamine) The sulfur counterpart to 2C-T-13. Synthesis has been taken to the nitrostyrene stage by Shulgin, producing “garish orange-red ‘Las Vegas’ colored crystals” which at the time of writing were “sitting on the shelf waiting to be reduced to the target compound”. It is unclear if the synthesis was completed, and no bioassays are publicly known.

2C-T-15 (SESQUI, 2,5-dimethoxy-4-cyclopropylthiophenethylamine) Similar to 2C-T-8, with the cyclopropyl group one carbon closer to the phenyl ring. This compound appears to have been unremarkable, with only threshold effects noted at 30mg. Like 2C-T-8, this “particular substitution pattern is not one to set the world on fire”.

2C-T-16 (2,5-dimethoxy-4-allylthiophenethylamine) Synthesis was taken to the nitrostyrene stage by Shulgin, but has not been completed to public knowledge.

2C-T-17 (NIMITZ, 2,5-dimethoxy-4-sec-butylthiophenethylamine) Dubbed “Nimitz” by Shulgin after State Highway 17 from Oakland to San Jose (the Nimitz freeway), now called Interstate 880. Active in doses of 60 to 100 mg, it produces a 10-15 hour experience with alteration of thought patterns but little visual distortion. This compound is also notable for possessing a secondary butyl group containing an asymmetric carbon atom. Only racemic 2C-T-17 has been bioassayed, but Shulgin was extremely curious if the activity of the compound could be isolated to one of the two stereoisomers. This would be similar to the isolation of psychedelic effects to the R isomers of the substituted amphetamines, with their asymmetric carbon next to the amine group on the other side of the phenyl ring. Both stereoisomers of 2C-T-17 were brought to the nitrostyrene stage, but the independent synthesis of the individual stereoisomers was never completed to public knowledge.

2C-T-18 (2,5-dimethoxy-4-cyclobutylphenethylamine) Synthesis was taken to the nitrostyrene stage by Shulgin, but has not been completed to public knowledge.

2C-T-19 (2,5-dimethoxy-4-n-butylthiophenethylamine) Synthesis was taken to the nitrostyrene stage by Shulgin, but not completed to public knowledge.

2C-T-20 (2C-T-3, 2,5-dimethoxy-4-(beta-methallyl)thiophenethylamine) Also known as 2C-T-3. Before working on the 2C-T series Shulgin investigated a similar series of promising compounds dubbed the Alephs, of which Aleph-3 was the beta-methallyl homologue. The synthesis of Aleph-3 was attempted, abandoned, and eventually forgotten. Years later the idea came to Shulgin again, and the beta-methallyl Aleph was begun anew along with the corresponding beta-methallyl 2C-T compound (2C-T-20). This led to the rediscovery of notes referencing the initial Aleph-3 synthesis attempt, and 2C-T-20 was renamed 2C-T-3 in order to maintain consistency with the Aleph project.

2C-T-21 (2,5-dimethoxy-4-(2-fluoroethylthio)phenethylamine
) The fluoroalkyl counterpart to 2C-T-7. Active in dosages between 8 and 12 mg it produces a 7 to 12 hour experience with a euphoric push. It was the first psychedelic compound synthesized which contained six separate elements, was widely regarded as a rich and unique material, and now languishes in obscurity due to an infamous incident that led to a large-scale DEA investigation.

On March 9, 2004, a 22-year-old quadriplegic man named James Edwards Downs in St. Francisville, Louisiana, consumed an unknown dose of 2C-T-21 by sticking his tongue into a vial of powder he had purchased online. He developed a high fever, had a tonic-clonic seizure, and slipped into a coma. Four days later, on March 13, Downs died at Lane Memorial Hospital in Zachary, LA.

This death became part of a two year DEA investigation called Operation Web Tryp which was launched in 2002. On July 22, 2004, the owners of American Chemical Supply were arrested on federal charges relating to distribution of controlled substance analogues and the death of James Edwards Downs.

2C-T-21.5 (2,5-dimethoxy-4-(2,2-difluouroethylthio)phenethylamine
) Shulgin refers to this compound at the end of the 2C-T-21 entry in PiHKAL.

And it has just occurred to me that there is yet another effort that is certainly worth making, inspired by the observation that 2,2-difluoroethyl iodide is commercially available and not prohibitively expensive. It, with 2,5-dimethoxythiophenol, and following the obvious steps to the aldehyde, the nitrostyrene, and the final amine, would produce 2,5-dimethoxy-4-(2,2-difluoroethylthio)phenethylamine hydrochloride. It lies exactly half way between the highly potent 2C-T-21 (the mono-fluoro), and the yet to be finished 2C-T-22 (the trifluoro). Let’s be weird, and call it 2C-T-21.5. I will wager mucho that it will be very potent.

Synthesis of 2C-T-21.5 has not been completed to public knowledge.

2C-T-22 (2,5-dimethoxy-4-(2,2,2-trifluouroethylthio)phenethylamine
) Synthesis was abandoned due to difficulties in purifying the aldehyde, and has not been completed to public knowledge.

2C-T-23 (2,5-dimethoxy-4-cyclopentylthiophenethylamine
) Synthesis was taken to the aldehyde stage by Shulgin, but has not been completed to public knowledge.

2C-T-24 (2,5-dimethoxy-4-diethylaminothiophenethylamine
) Shulgin’s synthesis of this compound was unsuccessful, and it was not given a name. Murple dubbed it 2C-T-24. Shulgin describes his attempt in PiHKAL:

One additional effort was made to prepare a 2C-T-X thing with a sulfur-nitrogen bond. The acid chloride intermediate in the preparation of 2,5-dimethoxythiophenol (as described in the recipe for 2C-T-2) is 2,5-dimethoxybenzenesulfonyl chloride. It reacted smoothly with an excess of diethylamine to produce 2,5-dimethoxy-N,N-diethylbenzenesulfonamide which distilled at 155 °C at 0.13 mm/Hg and which could be recrystallized from a 4:1 mixture of cyclohexane/benzene to give a product with a melting point of 41-42 °C and an excellent proton NMR. This amide proved totally refractory to all efforts at reduction, so the target compound, 2,5-dimethoxy-4-diethylaminothiophenethylamine, has not been made. It has not even been given a 2C-T-X number.

This was the second attempt at creating a sulfur-nitrogen bonded phenethylamine, the first being 2C-T-12 which was also unsuccessful.

2C-T-25 (2,5-dimethoxy-4-isobutylthiophenethylamine
) The isobutyl to 2C-T-4’s isopropyl, or an unfluorinated 2C-T-21.5. This compound was synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-27 (2,5-dimethoxy-4-benzylthiophenethylamine
) Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-28 (2,5-dimethoxy-4-(3-fluoropropylthio)phenethylamine
) The fluoroalkyl counterpart to 2C-T-19. Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-30 (2,5-dimethoxy-4-(4-fluorobutylthio)phenethylamine
) 2C-T-28 with an additional carbon in the alkyl chain. Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-31 (2,5-dimethoxy-4-(4-trifluoromethylbenzylthio)phenethylamine
) A 4-trifluoromethyl substituted 2C-T-27. Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-32 (2,5-dimethoxy-4-(2,3,4,5,6-pentafluorobenzylthio)phenethylamine
) A ring-fluorinated 2C-T-27. Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

2C-T-33 (2,5-dimethoxy-4-(3-methoxybenzylthio)phenethylamine
) A 3-methoxy substituted 2C-T-27. Synthesized by Daniel Trachsel but has not been bioassayed to public knowledge.

Trachsel, D. Synthesis of novel (phenylalkyl)amines for the investigation of structure-activity relationships. Part 2. 4-Thio-substituted [2-(2,5-dimethoxyphenyl)ethyl]amines (=2,5-dimethoxybenzeneethanamines). Helv. Chim. Acta, 5 Aug 2003, 86 (7), 2610–2619.