Posts Tagged ‘ research chemical

AM-2201 – A Hyperpotent Halogenated Unintended Consequence

With the recent legal issues surrounding certain synthetic cannabinoids in the United States, the market has changed. Instead of economic pressures selecting certain cheap to produce cannabinoids with desirable effects, legal pressures have now created a situation where the inelastic demand of recreational drug users causes overseas manufacturers to seek the highest potency compounds in order to minimize risk of seizure. People still want to buy it, but they want to minimize the number of transactions, so send the tiniest package with the largest value.

Previously in the market we saw various simple substitutions of the cheap, easy to synthesize, and potent original, JWH-018. But halogenated analogs, previously cast to the side due to more involved synthesis routes, are now becoming more popular due to the trend of increasing potency and duration. The difficulty in handling these very powerful compounds has caused them to be most prevalent in the commercial “smoke blends” market, where a fraction of these halogenated analogs can replace a far larger volume of the earlier generation cannabinoids. With these new legal pressures on end users however, we are seeing an increasing tendency toward the retail sale of these pure compounds.

The first of the halogenated AM series cannabinoids to reach the market was AM-694, discussed in Synthetic Cannabinoids: JWH-018 Replacements. This shares a fluoropentyl chain with AM-2201, and initially health concerns were raised about possible metabolism to toxic fluoroacetate. Luckily it appears that the odd-numbered (pentyl) chain means that the less toxic 3-fluoropropanoic acid will likely be produced instead, but this raises questions – if an even numbered fluoroalkylated chain was found to obscenely potent, would these health concerns prevent it from being brought to market? Or would the economic incentives of this crudely regulated market result in a product being sold with the excuse that only chronic long-term exposure is likely to result in apparent health risks? One would hope that manufacturers would not be so greedy, but history is not reassuring.

The effects of AM-2201 also appear to differ from natural cannabis and the first generation synthetic cannabinoids, both to start and as tolerance builds. Initially the effects are quite similar, although doses for AM-2201 are approximately a third of JWH-018. This has resulted in many reports of self-reported “seasoned” synthetic cannabinoid users having anxiety reactions as a result of apparent overdose due to increased sensitivity to inaccurate measurement. Tolerance builds quickly, and frequent users have reported psychedelic-style effects typically previously only associated with high-dose oral consumption of marijuana. The major difficulty with these high potency compounds is finding the “window” – that range of dosage where effects are strong enough to be considered enjoyable, but not so strong that peripheral effects such as anxiety or or dissociation affect the recreational potential. Measurement noise appears to translate to a rather inconsistently enjoyable experience.

It is frustrating that regulators appear to not consider the consequences of the time-tested inelastic demand of recreational drug users. Natural cannabis has been used for thousands of years with little ill effect, and its prohibition resulted in the birth of the synthetic cannabinoid market, compounds that have been known to science for at most a few decades. Now unthinking attempts to stamp out the first generation synthetic cannabinoid market have resulted in the promotion of hyperpotent substitutes patented in the mid-2000s. It is the very definition of unintended consequence to consider that regulatory promotion of these relatively unknown compounds could result in more public health concerns rather than less.

AIRCR Jumps the Shark

The Association of Independent Research Chemical Retailers (AIRCR) is a collection of largely UK based research chemical vendors who have banded together in a stated attempt at creating a self-regulating organization. The motivation apparently was a result of the wide-scale scams and misrepresentation of product that occurred as the easy money of mephedrone sales started to dry up due to government regulation.

A noble goal indeed, as even before this the research chemical scene as a whole was not exactly a shining example of professionalism and restraint. Self-regulating organizations have a strong track record in many fields including finance, law, medicine, and engineering, and can demonstrate the ability of the market to regulate itself without requiring explicit government oversight. They can also quickly shift from self-regulating to self-serving organizations as their structures may encourage monopolistic behavior and cronyism.

AIRCR initially appeared to sit almost precisely between these two extremes. There was no question that after the March 2010 ban of mephedrone in the UK many research chemical vendors scrambled to provide any substitute product at all to the seething masses who had gotten used to the cheap and staggeringly effective drug. Hyperpotent long-lasting toxic stimulants, existing (and now illegal) mephedrone stocks rebranded and sold with nonsense chemical formulas, and simply fake product had created mass disillusionment within many retail customers, and retailers began to panic as they saw sales volumes plummet.

The retail strategy of AIRCR seems to be best outlined by the approach of a group of several UK based websites who are now AIRCR members. Their first mainstream exclusive compound 6-APB (“Benzo Fury”) was based off the structure of the classic MDA. Correctly identifying that the major issues leading to prohibition of mephedrone were indiscriminate doses and widely available cheap product, 6-APB was produced in limited runs and pressed into “pellets” (not pills, which would imply human consumption and not “research” of course). Presumably the hope was that with a more expensive product divided up into an appropriate dose overconsumption would be less of an issue. By having a monopoly on production and controlling supply, the compound could be rationed via economic pressures to those most likely to use it correctly – and more importantly, to those least likely to create unwanted media attention. While less profitable month to month than the wide-scale sales of mephedrone, it would hopefully provide a more consistent cash flow, few competitive pressures, and a longer production run leading to a better structured business model.

For new recreational entheogens with limited reinforcing characteristics this business model, while far from perfect, is a rational approach to the current regulatory environment. Retail levels sales to end users are largely tolerated if media attention and underage use is limited, a sort of “don’t ask, don’t tell” of the drug world. But with their latest product, AIRCR has succumbed completely to the temptations of monopoly and have fixed a noose about their own neck.

The compound in question is literally trademarked by AIRCR as methiopropamine, presumably to distract from the more conventional nomenclature of methamthetamine. The similarity to the much-demonized methamphetamine is no coincidence, as it can be thought of as methamphetamine where the phenyl group is replaced by a sulfur-containing thiophene group. Typically the replacement of a phenyl with a thiophene in this class of compounds results in increased inhibition of VMAT, which can be correlated with increased reinforcement and addictive effects. Preliminary tests appear to indicate similar qualitative effects to methamphetamine, a shorter duration, slightly lower potency, and more peripheral effects including vasoconstriction and sweating.

It seems almost a foregone conclusion to say that sales of a research chemical with this level of behavioural reinforcement and close structural similarity to one of the most publicly demonized drugs of our time will not end well. Supply controls will likely be insufficient to limit media attention, and these very supply controls are likely to be quickly circumvented as synthesis and precursors will be vigorously investigated by other labs wanting to get in on a fast buck. A shame that the first public attempt at self-regulation in the research chemical industry could fall to temptation so quickly.

Farewell AIRCR, we hardly knew ye.

Synthetic Cannabinoids: JWH-018 4-Alkyl Substitutions

Ah, JWH-018. Trivial to synthesize, highly potent, and a formerly legal substitute for the world’s most popular contraband drug. No wonder it reached the heights of popularity it did, and no wonder that labs are currently scrambling to replace it. And just like in corporate pharmacology, small substitutions can create not only a new compound, but a new cash cow free of previous legal restraints.

So let’s look at the naphthyl ring of JWH-018 in particular, and number our possible substitution sites for clarity. We could try many approaches at many positions, but suppose we limit ourselves to the 4-position. The halogens are a possibility (JWH-398 can be thought of JWH-018 with a chlorine substituted here), but let’s try some alkyl chains and see if they come up winners.

For reference, JWH-018 has binding affinities of 9.00 nM at CB1 and 2.94 nM at CB2. If we were a lab, we’d be looking for higher potency compounds (lower binding affinities) since increased attention from law enforcement means the only rational choice is to pack as much punch as you can in the smallest package for transport. It might be nice to try to search for compounds with the most pleasant effects, but that seems to be rather idealistic in the cold light of this new day.

JWH-122 (CB1 Ki = 0.69 nM, CB2 Ki = 1.20 nM)
Our first try, and things are looking good. A drastic increase in potency based on binding affinities, slightly smaller doses compared to JWH-018, and similar effects. Duration also appears to increase with this substitution, making it an apparent winner all around.
JWH-210 (CB1 Ki = 0.46 nM, CB2 Ki = 0.69 nM)
Increasing the alkyl chain length by a carbon appears to produce little drastic change. A similar duration to JWH-122, with perhaps a slight decrease in potency. A stimulating and slightly trippy headspace.
JWH-182 (CB1 Ki = 0.65nM, CB2 Ki = 1.10 nM)
Should be quite potent based on binding affinities, but is not widely distributed in the marketplace. Perhaps perceived qualitative potency in human subjects decreases as the 4-alkyl chain length increases as seen in the move from JWH-122 to JWH-210, making this compound not economical to produce at this point in time.

Synthetic Cannabinoids: JWH-018 Replacements

On November 24, 2010, the DEA used its emergency scheduling authority to temporarily control JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol, synthetic cannabinoids used as cannabis substitutes. If history is any guide, this tempory control will soon become permanent. The major motivations for this action appeared to be twofold. First, use among members of the military had become increasingly prevalent as these compounds produced metabolites that did not flag typical drug tests. Secondly, the high potency and full agonism of certain compounds (particularly JWH-018) could lead to states of anxiety in higher doses. While a temporary mental state and not reflective of any physical toxicity, hospitals began reporting an increase in admissions and emergency calls from primarily inexperienced and younger users in the midst of a wigout. Despite a complete lack of quantifiable mental or physical harm, this led to media demonization as a “dangeous drug available to teens”.

So the DEA intervened, but there’s just one problem. The synthetic cannabinoids emergency scheduled are a tiny fraction of literally thousands of related compounds known to science – with more being discovered every day. So what are some of the cannabinoids currently on the market that slide in under the radar?

JWH-018 (CB1 Ki = 9.00 nM, CB2 Ki = 2.94 nM)
The most famous alkylated naphthoylindole, doomed to criminalization in the United States, and included here as a structural reference.
JWH-019 (CB1 Ki = 9.80 nM, CB2 Ki = 5.55 nM)
Poor JWH-019. An alkylated naphthoylindole just like its butyl (JWH-073) and pentyl (JWH-018) brothers, they rose to fame while it languished in obscurity. A less anxiety prone and more cerebral headspace combined with a marginal decrease in potency relative to JWH-018 could lead to the last still-legal homologue of the family finally getting its dues.
JWH-081 (CB1 Ki = 1.20 nM, CB2 Ki = 12.4 nM)
If we look at the structure of JWH-081, we can see that it is very similar to JWH-018 with the exception of the methoxy group. Unlike JWH-018 however, it is more selective for the CB1 receptor which appears to be correlated with reduced anxiety (like JWH-073). A less trippy headspace with more physical stoning effects, and mild euphoria.
JWH-250 (CB1 Ki = 11 nM, CB2 Ki = 33 nM)
Replace the notorious napthalene ring of JWH-018 with a 2′-methoxyphenylacetyl group and you get JWH-250, a rising star. Unlike other synthetic cannabinoids which produce a more indica-style headspace, JWH-250 produces an effect somewhat similar to JWH-018 with a clear, soaring, sativa charactered stone.
RCS-4 (BTM-4, SR-19) (CB1 Ki = ?? nM, CB2 Ki = ?? nM)
With a structure reminiscent of JWH-081 if we chopped its napthyl in half to produce a phenyl group, this synthetic cannabinoid has similar potency and effects to JWH-018, all allegedly without legal issues or the infamous JWH “fear”. Interestingly enough this seems to be the result of independent research seeking new psychoactive (and profitable) cannabinoids, and not simply someone pinching from academic journal articles. Prohibition made the production of these cannabinoids a huge cash cow, and now a self-sustaining independent industry with very credible players has been born.
AM-694 (CB1 Ki = 0.08 nM, CB2 Ki = 1.44 nM)
A hyperpotent cannabinoid based on CB1 binding affinity, with a fluorine on the end of the pentyl chain in an apparent attempt to increase duration of effect. This raised some eyebrows when it first appeared with concerns about possible metabolism to toxic fluoroacetate. Luckily it appears that the odd-numbered (pentyl) chain means that the less toxic 3-fluoropropanoic acid will likely be produced instead. The choice of this compound for wide distribution rather than other alternatives raises questions, as the emphasis on duration and potency seem to reveal a focus on profit rather than quality of headspace.

This should not be considered anywhere near a complete list of compounds currently available in the marketplace, and is an even tinier slice of the vast number known to produce pleasurable psychoactive effects. It seems unlikely that a blanket approach based on criminalization will be practical, as a large number of related compounds have demonstrated breakthrough benefit in treating afflictions such as Alzheimer’s and cancer. There is simply too much money to be made with these new medicines that would be caught in the net, and legislators are aware of this.

What seems more likely is an uneasy truce between synthetic cannabinoid producers and the DEA based on certain criteria. If the producers are sensible enough to avoid explicit sales to military personnel and teens resulting in decreased media attention, they will likely be ignored. Synthetic cannabinoids preparations sold on a retail level (“herbal incence” products) will likely be seized for “investigation” regardless of the legality of the active ingredient, as inventory tied up in evidence lockers will result in cost pressures almost as effective as an actual ban. Existing distributors are likely to move toward larger scale sale of explicitly unscheduled cannabinoids, allowing greed to motivate new smaller players to move into the now excessive scrutiny of retail level distribution.

Synthetic Cannabinoids: The Alkylated Naphthoylindoles

There are a huge variety of synthetic cannabinoids possible, including variations on THC and other natural cannabinoids, the CP series created by Pfizer in the 1970s but never brought to market, anti-Alzheimer’s treatment HU-210, and aminoalkylindole derivatives like WIN 55,212-2. But the most popular and prevalent synthetic cannabinoids in today’s recreational drug market are a subset of what are colloquially known as “JWHs”, after the researcher who completed a large body of work on them, John W. Huffman. There are several hundred of these compounds, named in the format JWH-001 and up. Some of the first compounds in this long list to be diverted to the recreational drug market are certain alkylated naphthoylindoles, which also happen to be very easy to synthesize. Have you used “herbal incense”, “Spice”, “K2”, or any of the other cannabis substitutes that have been popping up lately? A safe bet is that they’re an inactive herbal carrier with these synthetic cannabinoids dissolved in a solvent sprayed on top.

Synthetic cannabinoids sold in this manner drive a large and profitable industry, a strange bastard child of prohibition that would simply not exist if the sale of cannabis was regulated. While a small subset of informed drug users would likely still create demand for pure versions of these products, “incense” consumption would be effectively zero if the general population had access to quality cannabis and did not have to worry about metabolic products being tested for.

Imagine the state of the synthetic cannabis industry a few years ago. There have been whispers of some interesting cannabinoids being developed by academics for medical use and research. But how is it possible to tell which of these might substitute for THC in recreational users? Let’s investigate the binding affinity, a measure of how well a compound binds to a receptor. We can use Ki values to do this, which measure how concentrated the compound must be in order for it to have an equal chance of being bound to a receptor or not. Lower values mean high potency as only a small amount of compound is required, while higher values indicate lower potency. While having similar binding affinities doesn’t always mean similar recreational effects, it can certainly help narrow the field. Let’s see how the first seven alkylated naphthoylindoles stack up against THC.

Compound CB1 Ki (nM) CB2 Ki (nM) Image
THC
(reference)
40.7 ± 1.7 36.4 ± 10
JWH-070
(methyl)
>10000 >10000
JWH-071
(ethyl)
1340 ± 123 2940 ± 852
JWH-072
(n-propyl)
1050 ± 55.0 170 ± 54.0
JWH-073
(n-butyl)
8.90 ± 1.80 38.0 ± 24.0
JWH-018
(n-pentyl)
9.00 ± 5.00 2.94 ± 2.65
JWH-019
(n-hexyl)
9.80 ± 2.00 5.55 ± 2.00
JWH-020
(n-heptyl)
128 ± 17.0 205 ± 20

The shorter alkyl chain lengths of JWH-070 (ethyl) and JWH-071 (methyl) show negligible activity. As we move to the propyl chain of JWH-072 we see little change in CB1 binding affinity but CB2 affinity increases almost 15 times. JWH-073 and its butyl chain are a bit more promising, with higher affinity for CB1 and a similar affinity for CB2 compared to THC. JWH-018 (pentyl) and JWH-019 (hexyl) stand out, with higher potency at both receptors than THC itself. So far so good, but as we increase the chain length in JWH-020 (heptyl) our streak ends, as we see a a 13 fold decrease in binding affinity at the CB1 receptor and a 40 fold reduction at the CB2 receptor.

Activity appears to peak around the five carbon pentyl chain in these naphthoylindoles, as opposed to the classical cannabinoids which peak at the seven carbon heptyl chain. Judging from binding affinities It looks like JWH-073, JWH-018, and JWH-019 would be the best bets – so did any of them pan out?

JWH-018 is likely the world’s most popular synthetic cannabinoid, and was one of the first introduced for wide sale. It entered the public psyche in late 2008 when German company THC-Pharm identified it as a primary ingredient in the “Spice” herbal smoke blend. Quickly outlawed in Germany and several other European countries in early 2009, it has since gained popularity in other markets including the US. Active in smoked dosages of only a few milligrams, tolerance builds quickly revealing a dirty secret relative to natural cannabis. JWH-018 is a single compound active as a full cannabinoid agonist, while cannabis acts as a mixture of many phytocannabinoids including partial agonists and antagonists. This complex balancing act provides a safety net that JWH-018 lacks, as the synthetic compound can activate cannabinoid receptors in a far more specific and potent manner. For instance, GABA may be inhibited far more effectively than natural cannabis, leading to severe anxiety and reduced seizure threshold at high doses. This may be the origin of the infamous “fear” JWH-018 is known to induce in overdose.

JWH-073 is not as potent as JWH-018, but has arguably a more pleasant high with less anxious effects. After JWH-018 was outlawed in Germany, a seizure and analysis of a new batch of Spice shipped only 4 weeks after the ban showed that the manufacturers had quickly switched active ingredients to the uncontrolled JWH-073.

JWH-019 has not reached the same fame as the others likely due to timing and distribution rather than any real shortcomings. It was introduced to a more saturated market along with many other competing synthetic cannabinoids after JWH-018 and JWH-073 were banned in some areas. This is likely to represent the new normal, as a wide number of these compounds targeting various recreational effects pop in and out of the market depending on economic and legal factors.

Mie Mie Aung, Graeme Griffin, John W Huffman, Ming-Jung Wu, Cheryl Keel, Bin Yang, Vincent M Showalter, Mary E Abood, Billy R Martin, Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding, Drug and Alcohol Dependence, Volume 60, Issue 2, 1 August 2000, Pages 133-140, ISSN 0376-8716, DOI: 10.1016/S0376-8716(99)00152-0.

The Alkylated 2Cs

Alexander Shulgin investigated a large number of substituted phenethylamines, and dubbed one class with methoxy groups substituted on the 2 and 5 positions of the benzene ring the “2C”s, for the two carbon atoms between this ring and the amino group. A suprisingly large number of substitutions on the 3 and 4 positions demonstrated intruiging psychedelic activity, including halogenation at the 4 position. There are other possible substitutions as well, including the alkylated 2Cs, which are generally considered “deeper” psychedelics than their halogenated cousins, with complex visuals and a more analytical and challenging psychedelic state.

3 position: hydrogen

4 position: alkyl groups, consisting of only single bonded carbon and hydrogen atoms (methyl, ethyl, propyl, isopropyl)

2C-D (2,5-dimethoxy-4-methylphenethylamine) has the simplest alkyl substitution, a methyl group. Personally, I’m a bit confused why this isn’t called 2C-M, but I don’t get to name these things. Best known as as a “smart drug” at doses under 10mg, it has been reported to aid in learning but has produced inconsistent results in trials. Shulgin referred to it as “pharmacological tofu”, a substance that could be used to potentiate and extend the action of other materials without changing the experience significantly – similar to the manner in which tofu in a stirfry absorbs the surrounding flavors without contributing a significant taste of its own. At higher doses of 30-100mg it is a proper psychedelic in its own right, but this lower potency has contributed to a lack of relative popularity due to a higher cost per dose.

2C-E (2,5-dimethoxy-4-ethylphenethylamine) is currently the most well known of the alkylated 2Cs, a material Shulgin dubbed “difficult but worthwhile”. Typically taken orally in doses of 10-25mg, it produces a psychedelic state lasting 8-12 hours described as emotionally neutral by many. The dose-response curve is also significantly steeper than 2C-D, with 20mg subjectively producing an experience twice as powerful as 15mg, and quickly spiraling to undesirably intense states above 25mg. As one of the most visual and powerfully introspective phenethylamines, it has gained favor with those preferring the deeper psychedelic states produced by compounds such as LSD.

2C-P (2,5-dimethoxy-4-propylphenethylamine). As the length of the alkyl chain increases, potency and duration increase along with it. Oral doses of 5-15mg begin to show effect after 3 hours, and can last 10-16 hours. While the visual style is similar to 2C-E, the mental state is slightly deeper with a more stimulated feel. Doses of 2C-P were regarded with great caution due to a concise note by Shulgin indicating that 16mg was “clearly an overdose”. This cast fear in some and doubt in others, as no apparent toxic effects had been noted with dosage levels approaching this, although the dose-response curve for mental effects appeared even steeper than 2C-E. Shulgin responded to the statement in 2004 with the following clarification:

I contacted the person who tried the 16 milligram dose of 2C-P and who gave me the phrase, “16 mg was clearly an overdose, with the entire experiment labeled a physical disaster, not to be repeated.”

He checked his notes and shared more details that establishes context for this comment. When he was about eleven years old, he was sitting in his living room of his parent’s house, and a medium sized earthquake happened and knocked over some furniture including a full bookcase. This landed on his legs and hurt him very badly. Nothing was broken, but the pulled muscles made it painful to walk. This discomfort lasted for upwards of a year.

At the peak of the 2C-P trial (he about 45 years old at the time) he recalled and re-lived this frightening experience and there was extreme pain in his legs. No cardiovascular effects, or signs of toxicity. It was a childhood physical disaster that was re-lived and he had no wish to repeat that particular dose, as he didn’t want to repeat the pain. He did another experiment two weeks later, with 9 milligrams, and had a long-lived +++ but had no childhood memories!

This all took place in late 1985.

2C-iP (2,5-dimethoxy-4-isopropylphenethylamine) has had little testing in humans, was not investigated in PiHKAL, and existing reports are inconsistent. Some suggest it is effectively inactive, with a large (1-2 orders of magnitude) decrease in potency relative to 2C-P (similar to the relationship of DOIP to DOPR), while others describe an experience similar to 2C-E requiring 1.5x the material for a comparable (although longer lasting) experience. It seems likely that more reports will appear soon, and perhaps the effects of this rare material will become more clear with time.

What about the longer alkyl chains (butyl, pentyl, etc.)? To my knowledge, they have not been sufficiently tested in humans to draw any real conclusions about their activity at this point in time. Shulgin found that activity declined significantly with the butyl group in the substituted amphetamines (DOM ~ DOET ~ DOPR > DOBU), but the action in the 2C compounds may not be quite as clear. Combined with the increase in difficulty of synthesis and the infamous maxim “There’s ethyl and propyl, but butyl is futile”, 2C-BU and other related compounds are unlikely to gain popularity absent some surprises. In general, the alkylated 2Cs share a complex style of visual distortion and a similar psychedelic character – but potency per unit weight, duration, and steepness of the dose-response curve increase as the size of the first three normal alkyl groups grows.

The Halogenated 2Cs

Many phenethylamines can cause changes in consciousness or are involved in the natural neurochemistry of the brain itself, such as dopamine and norepinephrine. Alexander Shulgin described a wide variety of these compounds in his book “Phenethylamines I Have Known and Loved“, and one variant in particular seemed to stand out as a psychedelic superstar. If methoxy groups were substituted on the 2 and 5 positions of the benzene ring, a suprisingly large number of substitutions on the 3 and 4 positions demonstrated profound psychedelic activity. The particular group was dubbed the “2C”s, for the two carbon atoms between the benzene ring and the amino group.

A huge number of these compounds can be synthesized, and several groups stand out with a unique psychedelic character. One of these is the halogenated 2Cs, known for colorful “persian carpet” style visual patterning, peripheral effects including stimulation/sedation, a medium duration of 4-8 hours, and a generally more “shallow” psychedelic feel.

3 position: hydrogen

4 position: the highly reactive halogens (fluorine, chlorine, bromine, iodine)

2C-F (2,5-dimethoxy-4-fluorophenethylamine) is a rare compound, tested by only a few subjects and possibly inactive. Only doses of greater than 100mg produced reports of a possible shift in consciousness, but these reports were inconsistent and the shift, if any, was so mild as to be irrelevant for the purposes of further research.

2C-C (2,5-dimethoxy-4-chlorophenethylamine) has been tested more widely, but does not currently have mass appeal presumably due to its mild effect. Oral doses can range from 20-80mg, which produces a psychedelic state with a unique physical character described as “intensely relaxing”, a change from other halogenated 2Cs which tend to produce a stimulated state.

2C-B (2,5-dimethoxy-4-bromophenethylamine) produced the most consistently positive reviews of the halogenated 2Cs in initial tests, and was the first to gain popularity with the wider public. It was used in psychiatric therapy in the 1980s after being first synthesized by Shulgin in 1974 and found favor as a compound that produced a more predictable and empathetic state than other psychedelics like LSD or psilocybin. Word also quickly spread about other side effects, including a distinct erotic enhancement which led to the worldwide sale of 5mg tablets under the brand names Eros and Nexus. Doses from 15-35mg produced a unique psychedelic state characterized by mild stimulation and euphoria, and 2C-B quickly became a drug of choice in the underground. The transition from psychiatric aid to club drug doomed 2C-B to eventual illegality, as it is now internationally controlled under the UN Convention on Psychotropic Substances.

2C-I (2,5-dimethoxy-4-iodophenethylamine) was first sold widely by Dutch smart shops who introduced it as a replacement to the recently banned 2C-B in 2000. Slightly more potent with a dosage range of 10-25mg, it was a good substitute but not “quite there”. With a jitterier stimulant character and less consistent erotic effects it once again gained popularity on the club circuit, but was quickly banned in the Netherlands in 2003. While still legal in many areas of the world, it is unlikely to ever regain the critical mass of popularity 2C-B possessed.

2C-A (2,5-dimethoxy-4-astatophenethylamine) would be the next logical extension after iodine as we march down the periodic table – but the only problem is that astatine is the rarest naturally occurring element due to its radioactive nature and short half-life. Quite a stir was created among some in the research chemical market when it was finally announced that 2C-A would be available for sale, until it became clear that the date of the announcement was April 1st. Shulgin had this to say about 2C-A:

What might be speculated as to [2C-A’s] activity? Probably similar in potency to 2C-I, requiring maybe 10 or 20 milligrams. The duration would be dicey to measure, since the isotope with the longest known half-life is half decayed in about 8 hours, and the longest lived natural isotope (for those who insist on natural rather than man-made things) is half decayed in less than a minute. Two predictions would be pretty solid. You might have quite a job accumulating your 10 milligrams of Astatine, as the most that has so far been made at one time is only about 0.05 micrograms, approximately a millionth of the amount needed. And the second prediction? You would not survive the screaming radiation that would bombard you if you could get the needed 5 or 10 milligrams of radio-astatine onto that magic 4-position, and the resulting 2C-A into your tummy!

In general, the halogenated 2Cs share a unique style of visual distortion, have similar durations, and the character and depth of the psychedelic experience remains fairly consistent – but potency per unit weight and stimulant effects increase as we move up through the halogens by molecular weight.