Posts Tagged ‘ cannabis

Why Does Cannabis Potentiate Psychedelics?

It’s an effect that many psychedelic users are familiar with – at the tail end of trip, with the experience waning, smoking cannabis will tend to increase the psychedelic effects and “bring the trip back”. Similar effects occur on the comedown of drugs like MDMA. Why does this happen?

It appears that this may be a result of the interrelationship between the brain’s natural cannabinoid receptors and the GABA system.

Nerve cells are designed to fire repetitively, and are subject to a barrage of stimuli. The brain prevents itself from spiraling out of control into hyperexcitable states by inhibition, a way of “turning down the volume” in the brain. The major workhorse for this is gamma animobutyric acid, or GABA. In a strange parallel, the brain synthesizes GABA in one step from glutamate, the brain’s major excitatory neurotransmitter.

We know that cannabis gets us “high”, that it produces a general excitatory effect across many areas of the brain. First this was thought to be a result of cannabinoid (specifically CB1) receptors being expressed on glutamate receptors. This was not the case. Instead, they appear to be almost exclusively expressed on GABAergic neurons where they have an inhibitory effect.

So it seems that cannabis inhibits the inhibitor, and ends up having a general excitatory effect. In the same manner that a benzodiazepine or alcohol may dull a trip via direct GABA agonism, cannabis may increase the effects of a waning psychedelic due to GABA inhibition.

Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. N. Hajos et. al. European Journal of Neuroscience, Vol. 12, pp. 3239-3249, 2000.

Dr. Atomic’s Marijuana Multiplier

First published in the early 1970s, Dr. Atomic’s Marijuana Multiplier provides an illustrated walkthrough to produce high quality hash oil based on the methods described in Gold’s Cannabis Alchemy.

from Dr. Atomic’s Marijuana Multiplier. Larry S. Todd, 1974.

2003 International Narcotics Control Strategy Report – The Netherlands

Summary

The Netherlands continues to be a significant transit point for drugs entering Europe (especially cocaine), an important producer and exporter of synthetic drugs (particularly Ecstasy and amphetamines), and an important consumer of most illicit drugs. U.S. law enforcement information indicates that the Netherlands still is by far the most significant source country for Ecstasy in the U.S. The current Dutch center-right coalition has made measurable progress in implementing the five-year strategy (2002-2006) against production, trade and consumption of synthetic drugs announced in May 2001. For example, there has been a significant increase in Dutch seizures of Ecstasy pills from 3.6 million in 2001 to six million in 2002 (last year for statistics). In July 2003, the National Criminal Investigation Department (Nationale Recherche) was set up with the key objective of enhancing the efficiency and effectiveness of criminal investigations and international joint efforts against narcotics trafficking. Operational cooperation between U.S. and Dutch law enforcement agencies is excellent, despite some differences in approach and tactics. Dutch popular attitudes toward soft drugs remain tolerant to the point of indifference. The Dutch government and public view domestic drug use as a public health issue first and a law enforcement issue second.

Cocaine Couriers

Despite fierce political opposition, the Dutch Parliament approved Justice Minister Donner’s plan to close down Schiphol airport to cocaine smuggling from the Caribbean on December 10, 2003. An estimated 20,000-40,000 kilos of cocaine, destined primarily for the European market, are smuggled annually through Schiphol (Dutch cocaine use is estimated at 4,000-8,000 kilos annually – in 2001 and 2002, more than 3,500 drug couriers were arrested and some 10,000 kilos of cocaine seized at the airport). Donner hopes to achieve 100% interdiction of the drugs coming into Schiphol on targeted high-risk flights from the Netherlands Antilles, Aruba and Suriname. He told the Second Chamber of Parliament on December 3, 2003, that, as a result of the 100% controls of passengers, luggage, freight and aircraft, the number of drug couriers is expected to rise significantly, fearing inadequate law enforcement capacity to handle the number of arrests. According to Donner, this justifies a temporary adjustment in prosecution policy – a certain category of drug couriers will not be prosecuted. He explained that criteria would be drawn up, which will not be made public in the interest of criminal procedures. However, couriers failing to meet these criteria will be prosecuted. (Unconfirmed reports suggested that only smugglers caught with 3 kilos or more are prosecuted.) Donner stated that summoning drug couriers in court at a later date would not be a solution, because this would also put a heavy burden on the Dutch judiciary. He did pledge the Chamber an early assessment of his proposals. Relevant data of drug couriers will be made available to airlines, which will be responsible for taking special measures against these persons, including an indefinite flight ban. Despite opposition within Donner’s own Christian-Democratic Party (CDA), the Second Chamber adopted his proposals on December 10, 2003.

The plan went into effect on December 11, and, during the first five days, 120 couriers were arrested on flights from the Netherlands Antilles, of whom 31 were released without a summons after drugs were recovered. The remaining 89 cases are being investigated or prosecuted. In addition, 104 potential passengers were turned away by the airlines and 375 passengers did not turn up. About 120 kilos of drugs were seized. During routine checks on flights from Suriname, 22 couriers were arrested, one of whom carried 14.5 kilos of cocaine.

Ecstasy Offensive

In July 2003, Justice Minister Donner published a progress report on the implementation of the five-year (2002- 2006) action plan against production, trade, and consumption of synthetic drugs. According to the report, six million Ecstasy pills were seized in 2002 compared to 3.6 million in 2001, and the number of dismantled Ecstasy laboratories rose to 43 in 2002 from 35 in 2001. The increase in Ecstasy seizures was attributed to intensified controls at Schiphol airport by the special team of Dutch customs and the military police (more than one million pills seized there in 2002), the introduction of five special police Ecstasy teams (total manpower: 90), and increased staffing at the Fiscal Intelligence and Investigation Service-Economic Control Service (FIOD-ECD). The progress report shows that the measures announced in the action plan are well underway. According to the 2002 annual report of the Unit Synthetic Drugs (USD), the five XTC teams conducted 36 investigations in 2002 and arrested some 76 suspects.

The chemical precursor PPK is the principal precursor used by Dutch Ecstasy laboratories. It comes mainly by sea from China through Rotterdam port. Due to human rights concerns, the Dutch government shares only limited information of an administrative nature with China. A Memorandum of Understanding formalizing this information- sharing arrangement was submitted to the Chinese in October 2003. No response has yet been received. The MOU states that China will keep the Netherlands informed regarding the progress and results of investigations that have been instigated on the basis of this administrative information. In addition to working directly with the Chinese, the Netherlands is an active participant in the INCB/PRISM project’s taskforce.

Cannabis

According to the fourth survey on coffeeshops in the Netherlands, published in October 2003, there were 782 officially tolerated coffeeshops at the end of 2002, which is a 3 percent drop over 2001, principally in the four major cities. About 73 percent of Dutch municipalities do not tolerate any shops at all, according to the study. In early 2004, Justice Minister Donner, whose CDA party has advocated closing of coffeeshops, is expected to publish a Cannabis Policy Paper, which should discourage cannabis use.

The 2002 National Drug Monitor shows that the number of recent (last-month) cannabis users in the Dutch population over the period 1997-2001 rose from some 326,000 to 408,000, or 3 percent of the Dutch population of 12 years and older (of a total population of 16 million). The largest increase is reported among young people aged 20-24, while use among the 12-15 year-old age group remained limited and hardly changed from 1997. Life-time prevalence (ever-use) of cannabis among the population of 12 years and older rose from 15.6 percent in 1997 to 17 percent in 2001. The average age of recent cannabis users is 28 years.

On November 27, 2003, the Netherlands agreed on an EU framework decision on harmonized sentencing of drug traffickers. Under the agreement, the maximum penalty for possessing a small quantity of cannabis will be raised from one month to one year imprisonment. The agreement, if ratified by Dutch parliament, would allow the Netherlands to maintain its coffeeshops.

Medicinal Cannabis

Since March 17, 2003, doctors are allowed to prescribe their patients medicinal cannabis. Two suitable government-controlled cannabis growers have been contracted, and, as of September 2003, the drug can be bought from pharmacies. The Health Ministry’s Bureau for Medicinal Cannabis controls quality and organizes the distribution. According to the Health Ministry, cannabis may have a favorable effect on seriously ill patients but the government recognizes the therapeutic effects of medicinal cannabis have not been proved and research continues.

Cultivation and Production

About 75 percent of the Dutch cannabis market is Dutch-grown marijuana (Nederwiet), although indoor cultivation of hemp is banned, even for agricultural purposes. Amsterdam University researchers estimate that the Netherlands has at least 100,000 illegal home growers of hashish and marijuana, with the number increasing. Together they produce more than 100,000 kilos of soft drugs and are the largest suppliers of coffeeshops, according to the study. The estimates are based on a significant rise in the number of lawsuits and police raids. Although the Dutch government has given top priority to the investigation and prosecution of large-scale commercial cultivation of Nederwiet, tolerated coffeeshops appear to create the demand for large-scale commercial cultivation.

The Netherlands remains one of the world’s largest producers of synthetic drugs. In 2002, the USD registered a total of 740 seizures of synthetic drugs around the world, of which 205 (some 30 percent) took place in the Netherlands. Of the remaining seizures registered in 35 other countries, some 70 percent could be related to Dutch criminal organizations. Of the 205 Dutch seizures, 141 involved synthetic drugs that were intended to be exported. The seizures of drugs around the world that could be related to the Netherlands involved some 24.6 million MDMA tablets and over 910 kilos of MDMA power. Of this total, the largest amount was seized in the Netherlands (6.1 million pills), Belgium (more than 5 million pills), followed by Germany (almost 3 million), the U.S. (2.5 million), France (2 million) and the UK (1.8 million). The USD reported lower amphetamine seizures in 2002 than in 2001, but the quantity of Dutch-related amphetamine seized in other countries went up. In 2002, the USD dismantled 43 production sites for synthetic drugs, of which 26 were situated in residential areas. Most production sites were MDMA laboratories. According to the USD, the production of synthetic drugs in residential areas is an alarming development. The FIOD-ECD, which is primarily responsible for intercepting chemical precursors, seized some 318 liters and 9,255 kilos of PMK and 1,228 liters of BMK in 2002.

Drug use among the general population of 12 years and older, 1997 and 2001 (life-time (ever) use and last-month use)

  Life-time use (%) Last-month use (%)
1997 2001 1997 2001
Cannabis 15.6 17.0 2.5 3.0
Cocaine 2.1 2.9 0.2 0.4
Amphetamine 1.9 2.6 0.1 0.2
Ecstasy 1.9 2.9 0.3 0.5
Hallucinogens 1.8 1.3 0.0 0.0
   of which LSD 1.2 1.0
Mushrooms 1.6 2.6 0.1 0.1
Heroin 0.3 0.4 0.0 0.1

Drug Seizures, source Europol

2001 2002
Heroin (kilos) 739 1,122
Cocaine (kilos) 8,389 7,968
Cannabis resin (kilos) 10,972 32,717
Herbal cannabis (kilos) 22,447 9,958
Ecstasy (tablets) 3,684,505 6,878,167
Amphetamine (kilos) 579 481
LSD (doses) 28,731 355

Cable Reference ID 04THEHAGUE4, 2004-01-02, Classification UNCLASSIFIED, Origin Embassy The Hague.

Casablanca’s Cafe Culture

A diplomatic cable was sent in May 2008 from Casablanca describing external, internal, and underground sources of wealth in Morocco.

Most Casablancans acknowledge that at least some of Casablanca’s wealth comes from illicit activities such as drug-trafficking and money laundering. In the words of [name removed], “We have dirty money. The problem is we don’t know how much.” Statistics do not exist to quantify how much of Casablanca’s wealth can be traced to illicit activities. However, one indication can be found in the USG’s own 2007 International Narcotics Control Strategy Report: “Morocco is the world’s biggest producer of cannabis resin (hashish) and is consistently ranked among the world’s largest producers of cannabis.” The report estimates that Morocco’s drug trade (mostly to Europe) nets about USD 13 billion per year, more than twice the amount brought in by tourism in 2007. Some portion of this money finds its way to Casablanca, where it is either spent on jewelry, cars, houses and other items, or it is laundered. Referring to the use of cafes as fronts for illegitimate business activities, one finance professional joked that “money laundering creates a nice cafe culture in Casablanca.”

From Cable Reference ID 08CASABLANCA104, 2008-05-23 16:04, Classification CONFIDENTIAL, Origin Embassy Casablanca.

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.

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.

Endocannabinoids

The precise mode of action of cannabis was unclear until very recently. In 1988 cannabinoid receptors were shown to exist in a rat brain, and in 1990 the locations of the cannabinoid receptor system were mapped in several mammalian species, including man. This led to the search for endogenous cannabinoids (endocannabinoids), natural compounds synthesized within the brain that would activate these same receptors. Several were discovered, with anandamide and 2-AG receiving the most attention. It was found that endocannabinoids operate via retrograde signalling, where a signal travels in reverse from a postsynaptic neuron to a presynaptic one. Unlike other neurotransmitters such as the monoamines which are stored in vesicles for eventual release after synthesis, endocannabinoids are created “on demand” by enzymes as required.

Anandamide (AEA) was first isolated in 1992 and named after ananda, the Sanskrit word for bliss, and the amide chemical backbone. Like all of the endocannabinoids, it is made from arachidonic acid in our bodies, an essential polyunsaturated omega-6 fatty acid that must be consumed as part of a complete diet. Anandamide is a full agonist at CB1 receptors with a potency comparable to THC, and a partial agonist at CB2 receptors. It is very common, found in nearly all tissues and in a wide range of animals.

2-arachidonoyl glycerol (2-AG). No one really wants to admit it since anandamide was discovered first and has such a great name, but 2-arachidonoyl glycerol is probably chiefly responsible for endocannabinoid signaling. A full agonist at both CB1 and CB2 receptors, it is capable of stimulating higher G-protein activation and is present at significantly higher concentrations in the brain than anandamide.

2-arachidonyl glyceryl ether (noladin ether) was first discovered in the brain tissue of a pig in 2001, and prior to this had been synthesized in a lab as a closely related analog of 2-AG. It binds primarily to the CB1 receptor with weak agonism at the CB2 receptor, and is more metabolically stable than 2-AG resulting in a longer half life.

N-arachidonoyl-dopamine (NADA) Discovered in 2000 in the brain of rats, NADA preferentially binds to the CB1 receptor with no action at dopamine receptors. It the amide of the neurotransmitter dopamine and arachidonic acid, as well as a potent inhibitor of the growth of breast cancer cells.

Virodhamine (OAE) can be thought of as similar in structure to anandamide where the nitrogen and oxygen atoms have switched places. The molecule was therefore named virodhamine after the Sanskrit word virodha meaning opposite. It is a partial agonist at the CB1 receptor and a full agonist at the CB2 receptor. It is present in concentrations comparable to anandamide in the hippocampus, but is present much higher concentrations in peripheral tissues with CB2 receptors.

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.