Posts Tagged ‘ research chemical

4-Hydroxy Tryptamines

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.

Leminger’s Scalines

Otakar Leminger was a little-known Czechoslovakian chemist who worked for years in industry and lived on the banks of the Elbe River in Ústí north of Prague. When he retired in the early 1970s he published a paper entitled “A Contribution to the Chemistry of Alkoxylated Phenethylamines” in which he describes the synthesis of several novel phenethylamines which he tested on himself to determine activity.

(1) allylescaline, 3,5-dimethoxy-4-allyloxy-phenethylamine (2) proscaline, 3,5-dimethoxy-4-n-propoxy-phenethylamine (3) escaline, 3,5-dimethoxy-4-ethoxy-phenethylamine (4) MAPEA, 3-methoxy-4-allyloxy-phenethylamine (5) MEPEA, 3-methoxy-4-ethoxy-phenethylamine

We can classify the compounds he discussed into two groups depending on the number of ring substitutions. Allylescaline, proscaline, and escaline have three while MAPEA and MEPEA have two. Generally phenethylamines with two ring substitutions are not active, but Leminger had found some exceptions. This knowledge might have been lost to time if not for the fact that Stanislov Wistupkin brought the paper to the attention of Alexander Shulgin.

[MAPEA and MEPEA are some] of the few phenethylamines with only two substituents that show even a hint of central activity. And there is an interesting story attached. I got a call out of absolutely nowhere, from a Stanislov Wistupkin, that he had discovered a number of new psychedelic drugs which he would like to share with me. They were simple phenethylamines, one with an ethoxy group at the 4-position, and one with an allyloxy group there. Both, he said, were mood elevators active between 100 and 300 milligrams. One of them was a material called MEPEA, and the other one was 3-methoxy-4-allyloxyphenethylamine, or MAPEA. When I did meet him in person, he gave me a most remarkable publication which had been authored some ten years earlier, by a person named Leminger, now dead. It was all in Czech, but quite unmistakably, right there on the third page, were the structures of MEPEA and MAPEA, and the statement that they were active at between 100 and 300 milligrams.

– Alexander Shulgin

MAPEA and MEPEA are only mildly active and interesting mostly in the sense that they appear to be the exception to the rule that phenethylamines with two ring substitutions are inactive. Leminger also created several mescaline variants with three ring substitutions by modifying the methoxy group at the 4 position and replacing it with an allyloxy, propoxy, or ethoxy group. The resulting compounds allylescaline, proscaline, and escaline were then tested on himself and found to be much more potent and intriguing.

Physiological effects of the compounds were examined only approximately on my body. The sulphate salts of MEPEA and MAPEA in doses 0.1-0.3 g were mild mood-elevators and were also cough calming agents. Allylescaline, proscaline, and escaline were much more active. Qualitatively there wasn’t a big difference among them and quantitatively their effect decreased: allylescaline was more potent than proscaline, and proscaline more potent than escaline. As an example the allylescaline experience is described:

“One hour after a 20 mg dose of allylescaline: perhaps slight vertigo, light drunkeness and pleasant excitation with locomotion need was observed. Eye perceptions were pricked up, colours seemed to be more warm and objects more plastic. Surroundings were much more interesting than usual. Colourful hallucinations were observed in the dark. Moreover, a calming effect to the breathing system and some kind of constriction of the digestive system was observed. Sleep at night was restless with megalomaniacal fantasies. Even 12 h after administration the effects were present. More serious studies of physiological activity are in contemplation.”

– Otakar Leminger

Leminger was the first to synthesize and consume allylescaline, the most potent of the mescaline derivatives explored. He was able to identify active phenethyamines with only two ring substitutions, a notoriously unproductive class of compounds. Did he conduct additional experimentation and screening beyond that detailed in this paper? No other publications by Leminger relating to psychedelic compounds are known.

Might there be other treasures that he had discovered, and never published? Was young Wistupkin a student of his? Are there unrecognized notes of Otakar Leminger sitting in some farm house attic in Northern Czechoslovakia? I extend my heartfelt salute to an almost unknown explorer in the psychedelic drug area.

– Alexander Shulgin

Otakar Leminger, A Contribution to the Chemistry of Alkoxylated Phenethylamines – Part 2. Chemicky Prumysl 22, 553 (1972).

Alexander Shulgin, #2 Allylescaline. Phenethylamines I Have Known and Loved, Transform Press (1991).

Alexander Shulgin, #123 MEPEA. Phenethylamines I Have Known and Loved, Transform Press (1991).

N-Alkylated Tryptamines

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.

methyl ethyl propyl isopropyl
(none) NMT NET NPT NiPT
methyl DMT MET MPT MiPT
ethyl DET EPT EiPT
propyl DPT PiPT
isopropyl DiPT

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.

Alpha Substituted Tryptamines

The tryptamine backbone provides a building block for a large number of research chemicals. One such class is the alpha-substituted tryptamines. There are two carbons between the amine group (NH2) and the indole ring of tryptamine, referred to as alpha and beta.

Short alkyl chains have successfully been substituted at the alpha position nearest the amine group. These include compounds such as AMT and AET, which are releasing agents of serotonin, norepinephrine, and dopamine resulting in stimulating and euphoric effects. At higher doses their psychedelic character becomes more prominent. Potency decreases as alkyl chain length increases, and alpha-propyltryptamine has not been widely explored.

What about substitution on the beta carbon instead? It doesn’t seem hopeful. Substitution at the alpha carbon acts to protect the compound against enzymatic degradation but the beta position does not have this advantage. Little actual data regarding synthesis or effects are available however, and this remains an unexplored possibility.

Non-LSD Ergoloids

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.

The Secret Life of Legal Highs

The research chemical market has exploded in recent years primarily due to the emergence of cheap euphoric stimulants produced in volume. The wide appeal and behavioral reinforcement of these compounds relative to the more niche appeal of previous psychedelic research chemicals resulted in a flood of cash from a less discerning clientele. If it made you feel good, it sold – and governments across the world quickly attempted to fill in the blanks in their legislation.

The market has now fragmented, with apparently new compounds popping up based on novel and not explicitly illegal backbones such as the aminoindanes. The effects are touted as nearly identical to older, now illegal alternatives however, and many retail user reports bear this out. This is in contrast to reports from experienced researchers with verified compound, who describe the new aminoindanes such as 5-IAI as effectively worthless.

So why the difference? How can there be such a distinction between reported effects, where a compound that has been found to produce weak threshold effects at best in a controlled setting sell like hotcakes in the retail market? A new research paper provides a rather convincing answer – the “new” retail products simply contain outlawed compounds, and are rebranded with an arbitrarily selected compound name that has some association as a possible replacement.

Seven samples of “new” legal highs were purchased online from multiple sources, sold as MDAI, “benzo fury”, 5-IAI, NRG-3, and E2. They were analyzed using GC-MS, and the results are shocking.

Sold As Active Compounds Identified
MDAI BZP, 3-TFMPP, caffeine.
MDAI MDAI
MDAI BZP, 3-TFMPP, caffeine.

Three samples of “MDAI” were tested. Only one actually contained MDAI, while the other two contained a mixture of caffeine and the illegal piperazines BZP and 3-TFMPP.

Sold As Active Compounds Identified
Benzo Fury BZP, 3-TFMPP, caffeine.
5-IAI BZP, 3-TFMPP, caffeine.
NRG-3 BZP, 3-TFMPP, caffeine.
E2 Caffeine

The results for the other products are equally depressing, none of which match the label. Three samples once again contained a mixture of BZP, 3-TFMPP, and caffeine, while one (E2) only contained large amounts of caffeine. Most interesting was the fact that correlation between various samples was extremely high – the same mixture of compounds was simply sold in differently labelled (and priced) bags!

These products were sold as legal (when they weren’t) and as new and novel different compounds (which they didn’t contain). This practice appears to be far more widespread than many would like to admit.

Baron, Mark and Elie, Mathieu and Elie, Leonie. (2011) Analysis of legal highs – do they contain what it says on the tin? Drug Testing and Analysis. ISSN 1942-7603 (Submitted)

Shulgin’s Sulfur Symphony – Part II

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.

2C-T-x Substitution Size and Potency

The 2C phenethylamines typically refer to the 2,5-dimethoxy 4-substituted phenethylamines. Generally, small lipophilic substitutions at the 4-position tend to produce compounds which act as agonists, while larger substitutions are partial agonists or antagonists.

This statement appears to be borne out by investigation of the 2C-T-x series of compounds developed and studied by Shulgin. If we sort compounds with entries in PiHKAL by molecular mass to obtain a rough measure of substitution size, we can graph the reported dosage ranges to help illustrate this relationship.

2C-T-15 is shown as a dashed line due to the fact that it was only tested at 30mg and found to be underwhelming with no upper range established, in contrast to the more rigorously established dosage ranges for other compounds. This lack of potency could be a consequence of the inclusion of the atypical cyclopropyl group, which is also found in the disappointing 2C-T-8.

2C-T, 2C-T-2, 2C-T-4, 2C-T-7 and 2C-T-21 have smaller substitutions at the 4-position and are considered rather potent psychedelics. Similar to the relationship of 2C-D (the smallest alkylated substitution) to the rest of the active alkylated 2Cs, 2C-T is less potent per milligram but has a very similar mental state to the previously cited compounds if dosage is adjusted upwards appropriately. As the substitution size grows, compounds like 2C-T-9, 2C-T-13 and 2C-T-17 are encountered which are less potent and not as classically psychedelic, most notably possessing decreased open-eye visual activity and an increased focus on stimulant effects relative to smaller substitutions even when dosage levels are adjusted for.

Phenylacetylindoles

The alkylated napthoylindoles were the first synthetic cannabinoids cheap and potent enough to make real noise on the recreational drug market. Concern was initially raised about metabolism of the naphthalene ring and resulting carcinogenic risk, which turned out to be validated (abstract O43) although perhaps initially overstated as it lies within a similar risk envelope as cigarettes. Compounds have now been produced that replace the naphthalene ring with a phenylacetyl group. These represent a new and unique class of synthetic cannabinoids, with applications as both replacements for banned cannabinoids and use as a possibly healthier alternative for informed users. Without substitution the structure is much less potent than JWH-018, but various substitutions at the 2, 3, and 4-position have been attempted. The 2-position substitutions demonstrate the highest potency as a class, and are outlined here.


JWH-167 (CB1 Ki = 90 ± 17 nM, CB2 Ki = 159 ± 14 nM) is shown here with JWH-018 and its naphthalene group in a light grey underlay for reference. Without any substitutions this base phenylacetylindole is not potent enough for sale on the recreational drug market, as it is roughly a tenth as potent as JWH-018 as measured by binding affinity.


JWH-251 (CB1 Ki = 29 ± 3 nM, CB2 Ki = 146 ± 36 nM). A methyl group at the 2-position increases potency, but binding affinities seem to be too weak for practical sale. This is contrasted with the facts that JWH-251 was found to be a component of certain Japanese “herbal smoke” blends and limited reports indicate this to be of somewhat similar qualitative potency to JWH-250. Time will tell if this compound will remain on the edge of the market or gain popularity.


JWH-250 (CB1 Ki = 11 ± 2 nM, CB2 Ki = 33 ± 2 nM). Currently the most popular phenylacetylindole. The 2-methoxy substitution produces a compound that is qualitatively slightly less potent than JWH-018, but produces a much more pleasant effect in higher dose ranges. As such, this compound has found favor with those who prefer a stronger cannabinoid experience without the near-certainty of anxiety in higher doses that JWH-018 was known to cause.


JWH-311 (CB1 Ki = 23 ± 2 nM, CB2 Ki = 39 ± 3 nM). Fluorine substitution provides the least potent outcome of the three halogens Huffman explored. Not widely available or tested.


JWH-203 (CB1 Ki = 8.0 ± 0.9 nM, CB2 Ki = 7.0 ± 1.3 nM). The most potent halogen substitution, and one of the most potent phenylacetylindoles along with JWH-250. Currently available for sale, but not widely explored.


JWH-249 (CB1 Ki = 8.4 ± 1.8 nM, CB2 Ki = 20 ± 2 nM). Slightly less potent than JWH-203, with a lower CB2 affinity that may be associated with reduced anxiety effects. Not widely available for sale, but could be waiting in the wings if JWH-203 takes off and is scheduled.

John W. Huffman, P. V. Szklennik, A. Almond, K. Bushell, D. E. Selley, H. He, M. P. Cassidy, J. L. Wiley, B. R. Martin, 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic indoles, Bioorganic & Medicinal Chemistry Letters, Volume 15, Issue 18, 15 September 2005, Pages 4110-4113, ISSN 0960-894X, DOI: 10.1016/j.bmcl.2005.06.008.

Burn it up, Thoughts on JWH-18 carcinogenicity, 01-05-2010, 02:22, Bluelight > Drug Discussion > Advanced Drug Discussion.

Shulgin’s Sulfur Symphony – Part I

The 2C class of psychedelic compounds first researched by Alexander Shulgin encompasses a wide range of mental experiences, but one substitution in particular seemed to resonate with the magic seen in legendary compounds like mescaline. Thioalkylation at the 4-position produced the famed 2C-T-2 and 2C-T-7, compounds noted for an almost overwhelming visual character with echos of the cosmic choir, and a dismantling of the ego more prominent relative to the perceptually focused halogenated and alkylated 2Cs. This unique experience caused Shulgin to focus his substantial talents on sulfur based substitutions at the 4-position for a period of time, producing a large number compounds named in the format 2C-T-x. The first twelve are outlined in this post.

One attribute of these compounds must be emphasized at the outset. Unlike the halogenated or alkylated 2Cs, sulfur substitutions appear to be correlated with varying degrees of MAO inhibition, which can cause significant health issues up to and including death in extreme doses or in combination with other recreational drugs, particularly stimulants. These compounds were used safely in reasonable oral doses for twenty years among a qualified group of explorers, but the research chemical surge of the early 2000s introduced these compounds to an untrained audience in pure bulk forms. With resellers actively encouraged not to disseminate information on safer consumption due to legal pressures to maintain an appearance of “not for human consumption”, reckless dosing and routes of administration led to tragedy.

2C-T-2 has been sold widely, and has not been involved in any fatalities to my knowledge presumably due to less significant MAOI effect as judged by euphoric “push” relative to the other sulfur substitutions. 2C-T-7 can be considered the most popular of the group, and has nonetheless been involved in at least three deaths involving either excessive insufflated doses over 30mg, use in combination with stimulants such as MDMA or ephedrine, or both. The less popular 2C-T-21 has produced one death after an extreme oral dose (sticking tongue in full vial of pure compound).

The desire to experience the mental state produced by these compounds should be weighed with the intentions, ability, and risk tolerance of the end user. A society which allows the purchase of firearms with the assumption of responsibility should allow the same for self-exploration, but this is often not the case. If you are unfamiliar with the mechanism of risk of these compounds (ie MAO inhibition), if you are unable to weigh these compounds accurately, and if you are unwilling to respect the impact of route of administration, then an alternative should be selected.

 

2C-T (2C-T-1, 2,5-dimethoxy-4-methylthiophenethylamine) Active in doses of 50-150mg, this compound produces a euphoric psychedelic experience for 5-6 hours that nonetheless was described as “generic” by Shulgin. Lack of potency relative to other closely related compounds and the somewhat shallow mental state make this a rare find on the research chemical market.

 

2C-T-2 (2,5-dimethoxy-4-ethylthiophenethylamine) Active in doses of 10-30mg, this compound produces a 6-8 hour experience most notable for its intellectual introspection, mescaline styled visuals, and unholy ability at higher doses to cause physical distress including nausea during the first hour of the experience. Like mescaline, after the purge a sense of contentment develops and the experience then progresses naturally. 2C-T-2 first rose to wide fame after the banning of 2C-B, and was first sold by Dutch smartshops as a substitute in 1997. As it produced a much richer and deeper psychedelic experience than 2C-B, it did not have as wide an appeal on the club circuit, but still sold widely enough that it was eventually banned by Dutch authorities.

 

2C-T-3 (2C-T-20, 2,5-dimethoxy-4-(beta-methallyl)thiophenethylamine) Also known as 2C-T-20. 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.

It is unclear if there was ever an “original” 2C-T-3 whose place was overwritten or shifted by insertion of the beta-methallyl. It is certainly an odd man out in the progression, as it would seem reasonable to place the n-propyl 2C-T-7 here after the ethyl 2C-T-2 and before the isopropyl 2C-T-4. A numbering system based on the previous Alephs appears to explain the gap, as perhaps the initial synthesis of the 2C-T-3 was simply left for later due to the increased difficulty relative to the alkyls surrounding it. The synthesis of 2C-T-3/2C-T-20 has never been completed according to public knowledge.

 

2C-T-4 (2,5-dimethoxy-4-isopropylthiophenethylamine) The isopropyl companion to the propyl substituted 2C-T-7. Active in doses between 8-20mg, it produces a long lasting change in mental state for 12 to 18 hours with a slight dissociative character. Human testing showed huge variance in responses, particularly in the subcategories of visual distortion and euphoric response. The inability to predict whether a 12+ hour long psychedelic experience would be euphoric and illuminating or dysphoric and anxiety ridden has contributed to a lack of recreational usage of this drug.

 

2C-T-5 (2,5-dimethoxy-4-cyclohexylthiophenethylamine) Has never been synthesized according to public knowledge, and was presumably based the similarly structured Aleph-5.

 

2C-T-6 (2,5-dimethoxy-4-phenylthiophenethylamine) Has never been synthesized according to public knowledge, and was presumably based the similarly structured and successfully synthesized Aleph-6.

 

2C-T-7 (2,5-dimethoxy-4-(n)-propylthiophenethylamine) Active in doses of 10-40mg with a duration of 8-16 hours, 2C-T-7 is perhaps the most popular of Shulgin’s sulfur substitutions likely due to a more consistent euphoric effect. A powerful psychedelic character lies underneath however, and initial hype about a easy to handle “candyflip” experience may have resulted in some overwhelming experiences. With nausea reported less frequently as a side effect in comparison to 2C-T-2, many cast 2C-T-2 aside as a shorter less euphoric 2C-T-7. This is not necessarily a valid critique, as the more euphoric mental state of 2C-T-7 often results in “sloppier” emotional analysis relative to the slightly more difficult and intellectual 2C-T-2. 2C-T-7 began its rise to fame in the summer of 1999 as Dutch smartshops began selling it in 7.5mg tablets dubbed “Blue Mystic” due to the success (and resulting ban) of 2C-T-2. Unsurprisingly, 2C-T-7 was quickly banned as well.

 

2C-T-8 (2,5-dimethoxy-4-cyclopropylmethylthiophenethylamine) Active in doses of 30-50mg and producing a 10-15 hour experience, this compound produces a mental state that many did not wish to repeat. Shulgin said in PiHKAL, “there are as many negatives as there are positives, and the particular substitution pattern is not one to set the world on fire.”

 

2C-T-9 (2,5-dimethoxy-4-(t)-butylthiophenethylamine) Active in doses of 60-100mg, it produces a 12-18 hour experience with significant peripheral body load and little psychedelic reward for the effort. Note that Wikipedia currently incorrectly refers to this as the n-butylthio substitution rather than the tert-butylthio referenced in PiHKAL, as the n-butylthio substitution should be referred to as 2C-T-19.

 

2C-T-10 (2,5-dimethoxy-4-(2-pyridylthio)phenethylamine) Synthesis was abandoned before completion, and has not been completed by others according to public knowledge.

 

2C-T-11 (2,5-dimethoxy-4-(4-bromophenylthio)phenethylamine) Synthesis was abandoned before completion, and has not been completed by others according to public knowledge.

 

2C-T-12 (2,5-dimethoxy-4-(1-morpholinothio)phenethylamine) Synthesis was abandoned before completion, and has not been completed by others according to public knowledge.

 

Sulfurous Samadhi, An Investigation of 2C-T-2 & 2C-T-7 by Murple, Feb 6, 2001.

Nichols, D. E. and Shulgin, A. T. (1976), Sulfur analogs of psychotomimetic amines. Journal of Pharmaceutical Sciences, 65: 1554–1556. doi: 10.1002/jps.2600651040