Archive for the ‘ Compounds ’ Category

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

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.

Decarboxylation of Cannabis

Natural cannabis contains a wide variety of phytocannabinoids, compounds which bind to cannabinoid receptors in the body and contribute to the high felt when cannabis is consumed. One interesting thing to consider is that the majority of these compounds do not dissolve in water, but were produced in a plant whose leaves and stems are saturated with water and require it to survive. So how were they biosynthesized in a plant if they are not soluble in water?

One proposed solution is that while in the living cells of the cannabis plant these cannabinoids are almost entirely present as their carboxylic acids which are water soluble.


Tetrahydrocannabinol (THC)
Insoluble in water, active in man.

Cannabidiol (CBD)
Insoluble in water, active in man in conjunction with THC.

Tetrahydrocannabinolic acid (THCA)
Soluble in water, inactive in man.

Cannabidiolic acid (CBDA)
Soluble in water, inactive in man.

After cannabis is harvested and cured, these carboxyl groups begin to degrade, releasing CO2 and leaving behind the desired decarboxylated active cannabinoids. Drying, aging, and heat all contribute to break this carboxyl group down, which is why fresh cannabis is typically cured and then smoked for maximum potency.

But what if you’re consuming the cannabis in a different manner, for instance in brownies or in an alcohol tincture? Then additional care must be taken to ensure the inactive cannabinoids such as THCA and CBDA are decarboxylated into the desired THC and CBD. This is especially important with lower quality cannabis that has not been properly cured, and will likely contain significant amounts of carboxylated cannabinoids as a result.

The good thing is that it’s quite easy to accomplish. Most recipes recommend heating ground cannabis in oil or butter, or a layer of roughly ground cannabis can be put on a baking sheet and put in a pre-heated oven at 200°F (~93°C) for five minutes which will dry and heat the cannabis sufficiently to improve the potency of the resulting product. This is especially important for alcohol tinctures, which typically are not heated as part of the preparation process unlike a baked good such as a brownie.

Phenethylamine and Amphetamine

Phenethylamine (phenyl-ethyl-amine): A phenyl ring, connected to an amine by an ethyl chain.

Phenethylamine is present in our nervous system, and is also the backbone of many psychoactive compounds including the neurotransmitters dopamine and norepinephrine and psychedelic compounds investigated by Shulgin in PiHKAL. It is sold as a nutritional supplement with stimulant effects as it acts as releaser of norepinephrine and dopamine in the brain, but is largely inactive due to extensive first-pass metabolism when taken orally ensuring very little passes the blood-brain barrier.

Amphetamine (alpha-methyl-phenethylamine): Phenethylamine methylated at the alpha carbon, the carbon closest to the functional amine group.

Amphetamine was first synthesized in 1887 by Lazăr Edeleanu as part of a series of compounds related to the herbal stimulant ephedrine. It rapidly increases the concentrations of dopamine, serotonin, and norepinephrine in the brain and has powerful motivating and euphoric effects. It has been used since its discovery to increase concentration and alertness, including World War II where British troops alone used 72 million amphetamine pills and today where Adderall is prescribed to children and adults diagnosed with ADHD.

Why is the line representing the methyl group wiggly instead of straight like you may be used to? Well, there are two possible stereoisomers of amphetamine that can be visualized more easily in 3D.


We can think of these as right and left handed versions – while they look identical at a glance, if we investigate their structure we cannot make them line up with each other no matter how much we rotate them around. We can think of the wiggly line as a methyl group coming out of, or going into, the page depending on the stereoisomer.

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.

Phytocannabinoids

Cannabinoids are a class of compounds which display activity at the cannabinoid receptor, and are named after the cannabis plant from which they were first isolated. There are at least two types of cannabinoid receptors. CB1 receptors are found mostly in the brain, but are not present in the medulla oblongata, a part of the brain stem responsible for respiratory and cardiovascular functions. This demonstrates a major safety feature of cannabis, that recreational use does not present a significant risk of respiratory or cardiovascular failure. CB2 receptors are expressed primarily in the immune system, and appear to be responsible for anti-inflammatory and anti-convulsive effects.

Phytocannabinoids are naturally occuring cannabinoids found in the cannabis plant. They are concentrated in a sticky resin secreted by trichomes, hairlike structures covering the plant and concentrated in the flowering buds where the plant’s precious seeds are located. Not unlike our own body hair, it provides a barrier for the plant against marauding insects and other parasites. The sticky resin also reduces the rate of water loss, similar to the waxy outer layer of a cactus. There are a handful of easily isolated phytocannabinoids which have received the most study, although many more are present in smaller quantities.

Tetrahydrocannabinol (THC) is the most well known phytocannabinoid of all, responsible for the majority of the recreational effects of cannabis when smoked. It is also more resistant to ultraviolet radiation than the other major phytocannabinoid CBD. Cannabis sativa is known for a higher ratio of THC to CBD and originates from hotter climates, which could be explained as a result of selection pressure from increased ultraviolet radiation in these equatorial regions. THC itself and sativas in general are known for a powerful, clean, and motivated high, but with possible anxiety occurring in higher dose ranges.

Cannabidiol (CBD) does not have the name brand recognition of THC, but can represent up to 40% of extracted cannabinoids in some strains. It has mild sedative effects on its own, and demonstrates significant antipsychotic activity. It shines in combination with THC, where it decreases undesirable effects such as anxiety and paranoia. Cannabis indica is known for higher levels of CBD relative to THC, and has a reputation for a more relaxed “couch lock” high rather than the racing intensity of the sativas. A survey of cannabis users also found those exposed to both THC and CBD has significantly lower introvertive anhedonia and psychosis risk scores relative to those exposed only to THC.

Tetrahydrocannabivarin (THCV) can be seen to be a close homologue of THC with a shorter sidechain. This psychoactive cannabinoid may be responsible for the differences in the unique high of “kush” and “haze” strains, and is found at levels of 5% to 50% of total cannabinoids in these strains. Interestingly enough THCV acts as an antagonist at the CB1 receptor, an action contrary to that of THC. This illustrates that the rich experience produced by cannabis cannot simply be isolated to a single compound.

Cannabidivarine (CBDV) is related to CBD in the same way that THCV is related to THC, a homologue with a shortened sidechain. It does not display clear activity in man, but is the biosynthetic precursor to THCV in cannabis. It is possible to isomerize CBDV to THCV under acidic conditions, similar to the manner that CBD may be isomerized to THC. This “isomerization” procedure was popular in the 1970s, with machines sold in magazines that supposedly could accomplish this at home.

Cannabinol (CBN) is the village idiot of cannabinoids. There is relatively little of it in a fresh plant, as it is produced by degradation of THC. Over time and exposed to factors such as light and air, potent THC in stored cannabis will be slowly converted to relatively inactive CBN. This can be prevented by properly curing cannabis (ensuring controlled moisture levels) and storing it away from direct light in a sealed container such as a lightly packed mason jar.