rational exploration of the underground

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.

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.

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 K_i 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.

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.