rational exploration of the underground

MDMA is one of the most popular illicit drugs in the world, and is unique relative to other stimulating drugs of abuse in that it possesses significant therapeutic potential and is less behaviorally reinforcing. Effects can be described as similar to both stimulants and classical psychedelics. This appears to be more than a simple qualitative description however, as the very geometry of the MDMA molecule seems to produce two distinct drugs.

It is easy to forget when looking at flat diagrams of molecules on paper, but these compounds exist in a three dimensional world. One of the consequences of this is the concept of chirality, or “handedness”. Both your left and right hand contain fingers, a palm, and a thumb which appear to be assembled in the same way - but they are not the same. We can put both of our palms downward - but our thumbs point in different directions. If we point our thumbs in the same direction, one palm faces up and the other down. No matter how hard we try, we cannot wave our hands around and make them line up together perfectly.

Something similar can happen to sufficiently complex molecules, and MDMA is one of these. There are two geometrically distinct enantiomers of MDMA.

Racemic MDMA is “normal” MDMA, a mixture of both.

In the late 1970s, Alexander Shulgin began to collect data about the subjective effects of these stereoisomers of MDMA. Various doses of R(-)-MDMA, S(+)-MDMA, and racemic MDMA were given to volunteers in doses from 40 to 200mg and the relative intensity of their reported experience rated zero to three on the Shulgin scale.

It soon became clear that a subjective difference in potency could be observed between the two stereoisomers. R(-)-MDMA was least potent, with only threshold effects observed between 100 and 200mg. Racemic MDMA caused full effects between 140 and 160mg, while S(+)-MDMA was most potent with full effects observed at 120mg. But was this difference in apparent potency the only distinction between the two?

Shulgin plotted the effects of racemic MDMA (red above) versus a simple average of the regressions he found earlier for R(-)-MDMA and S(+)-MDMA (black above). If the different stereoisomers differed only in apparent potency, these plots should be identical. Interestingly, they were not - with racemic MDMA quite literally reporting effects more than the sum of its parts. This was borne out by user reports as well. The S(+)-MDMA may have been more potent by weight at first glance, but alone it was more stimulating and lacked the indescribable “magic” of the full racemic MDMA experience.

Further investigation was undertaken by researchers including Kevin Murnane, who conducted experiments designed to further delineate the effects of each stereoisomer.

R(–)-MDMA	S(+)-MDMA
2C-T-7, a psychedelic phenethylamine, fully substituted for R(-)-MDMA in trained mice. DPT, a psychedelic tryptamine, acted as a partial substitute.	S(+)-amphetamine substituted for S(+)-MDMA in trained mice. Cocaine acted as a partial substitute.
In rhesus monkeys, R(-)-MDMA significantly increased prolactin levels.	S(+)-MDMA significantly increased both dopamine and serotonin levels.

In general, R(-)-MDMA appears to produce psychedelic effects and has a longer duration relative to the more stimulating effects of S(+)-MDMA. MDMA is an incredibly unique compound, where each stereoisomer has a distinct and centrally active mode of action. Unlike other compounds where one stereoisomer is more potent or responsible for the majority of effects, each stereoisomer of MDMA contributes to produce a full and complex experience.

Phenethylamines may be classified as stimulants (such as amphetamine where the S(+) entianomer is most active) or psychedelics (such as DOC where the R(-) entianomer is most active). MDMA appears to uniquely straddle this divide.

Shulgin, A.T. Personal Lab Notes (Book 2), page 238.

Murnane KS, Murai N, Howell LL, Fantegrossi WE. Discriminative stimulus effects of psychostimulants and hallucinogens in S(+)-3,4-methylenedioxymethamphetamine (MDMA) and R(-)-MDMA trained mice. J Pharmacol Exp Ther. 2009 Nov;331(2):717-23. Epub 2009 Aug 14.

Murnane KS, Fantegrossi WE, Godfrey JR, Banks ML, Howell LL. Endocrine and neurochemical effects of 3,4-methylenedioxymethamphetamine and its stereoisomers in rhesus monkeys. J Pharmacol Exp Ther. 2010 Aug;334(2):642-50. Epub 2010 May 13.

Dr. Rick Doblin of MAPS recently answered questions from the public, and I was lucky enough to be included.

Part 1 discusses his vision of a psychedelic future. Part 2 tackles “what can we do”, practical steps for the present.

Timothy Leary’s escape from prison seems to be torn straight from the script of a bad movie, but the best part is that it actually happened.

On January 21, 1970, Leary received a ten-year sentence for [possession of two marijuana roaches], with a further ten added later while in custody, for a previous [marijuana possession] arrest in 1965, twenty years in total to be served consecutively. When Leary arrived in prison, he was given psychological tests that were used to assign inmates to appropriate work details. Having designed some of the tests himself (including the “Leary Interpersonal Behavior Test”), Leary answered them in such a way that he seemed to be a very conforming, conventional person with a great interest in forestry and gardening. As a result, Leary was assigned to work as a gardener in a lower security prison, and in September 1970 he escaped. Leary claimed his non-violent escape was a humorous prank, and left a challenging note for the authorities to find after he was gone. For a fee, paid by The Brotherhood of Eternal Love, the Weathermen smuggled Leary and his wife, Rosemary Woodruff Leary, out of the United States and into Algeria.

The FBI didn’t seem to see the humor in the situation, as seen in part of the Weather Underground file. Their part in the escape was seen as evidence for “continuing foreign influence” of the movement.

The Weathermen couldn’t resist needling the government with a letter stating their involvement (Communique #4 referenced above).

After hopping from country to country, he was arrested on a plane in Kabul, Afghanistan, and returned to the United States.

He was then held on five million dollars bail. President Richard Nixon had earlier labeled him “the most dangerous man in America.” The judge at his remand hearing remarked, “If he is allowed to travel freely, he will speak publicly and spread his ideas.” Facing a total of 95 years in prison, Leary hired criminal defense attorney Bruce Margolin and was put into solitary confinement in Folsom Prison, California.

Leary made somewhat of a pretense of cooperating with the FBI’s investigation of the Weathermen and radical attorneys, by giving them information that they already had or that was of little consequence; in response, the FBI gave him the code name “Charlie Thrush”. Leary would later claim, and members of the Weathermen would later support, that no one was ever prosecuted based on any information he gave to the FBI.

Leary was released from prison on April 21, 1976, by Governor Jerry Brown. After briefly relocating to San Diego, Leary established residence in Laurel Canyon and continued to write books and appear as a lecturer and (by his own terminology) “stand-up philosopher.”

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.

Summary

[Kenyan] Attorney General Wako offers inconsistent, unconvincing explanations of why more than one ton of cocaine held by the Government of Kenya for over a year cannot yet be destroyed. [American Ambassador Wiliam Bellamy] and [British High Commissioner Adam Wood] agreed with the [British Government] to give the [Government of Kenya] another 3 weeks to develop a credible plan before going public with [their] dissatisfaction. Although many have called for Wako’s resignation in recent months, [Kenyan] President Kibaki does not have the constitutional authority to remove the Attorney General from office.

Wako explained that due to a “bad law” (specifically, section 74(a) of the Narcotic Drugs and
Psychotropic Substances Control Act), the [Government of Kenya] could not destroy the drug stockpile until it had been exhibited to, and sampled in the presence of, all of the defendants in the case. This has already occurred for six defendants currently standing trial in Nairobi. Another key defendant, however, has just been convicted on drug charges in the Netherlands. While the Netherlands has agreed to Kenya’s request for extradition, the defendant had appealed to the Netherlands high court. The High Court is expected to decide within the next two or three weeks whether the defendant can be extradited.

Wako said once the defendant is extradited, he will confront the evidence (the stockpile) and, after that, the stockpile can be disposed of. Wako was vague on how long this process might take. If, on the other hand, the Dutch High Court ruled against extradition, there would be no need to retain the stockpile.

[British High Commissioner Adam] Wood and I both pressed for the [Government of Kenya] to at least invite in outside experts to test, measure and seal the stockpile. This could be done immediately, and without prejudice as to how and when the stockpile was eventually disposed of. Such verification was needed, we argued, to put to rest worries that the stockpile had been tampered with and possibly trafficked. [British High Commissioner Adam] Wood explained how, with shipments of cocaine showing up in London on incoming Kenya Airways flights, [the British government’s] patience was growing thin. I added that the [Government of Kenya] would soon have a serious credibility problem if it could not show that the stockpile was intact and being handled in accordance with best international practices.

Unfortunately, Wako explained, it would not be a good idea to test, measure or seal the stockpile. It would undermine the prosecution’s case since it would allow the defense to argue that the State did not have confidence in its own evidence. Wood and I dismissed this argument as lacking any credibility. When pressed about whether retention of the entire stockpile was necessary throughout the trial, Wako and Tobiko were evasive. Eventually, they admitted that the stockpile could be disposed of once the prosecution rested its case.

Comment

The bottom line is that the Kenyan authorities have been sitting on more than a ton of cocaine for more than a year, at least four consignments of cocaine have reached the U.K. from Kenya in that period, and no one in the [Government of Kenya] is able or willing to assert that the stockpile is intact and that a credible plan exists for measuring and disposing of it. It is significant that Police Commissioner Ali, under whose authority the cocaine is supposedly safeguarded, urged us prior to the Wako meeting to press the Attorney General hard for verification as soon as possible. Ali wants to wash his hands of the mess; for some reason, Wako does not.

[American Ambassador Wiliam Bellamy and British High Commissioner Adam Wood] have heard repeated complaints from respected figures in and out of the [Government of Kenya] (including Anti-Corruption Chief Justice Ringera and World Bank Director Colin Bruce) that Wako is the main obstacle to successful prosecutions of any kind in Kenya. Whether he is profiting in some way from the drug trade, protecting others who are involved in it, or is working from some other motive, we cannot tell. He may feel a degree of immunity since the constitution does not allow the President or any other authority to remove him from office.

Attorney General Wako is also notable for his involvement in the Goldenberg scandal, which some estimate to have cost Kenya more than 10% of its annual gross domestic product.

From Cable Reference ID 06NAIROBI839, 2006-02-24 , Classification CONFIDENTIAL, Origin Embassy Nairobi