What’s the buzz?: Synthetic marijuana, K2, Spice, JWH-018

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My field of natural products pharmacology was founded by indigenous cultures who recognized that plants and fungi contain compounds that produce altered states of consciousness, leading to their most common use in religious ceremonies. While we may most often associate these naturally-occurring drugs with hallucinogens, the arguably most common natural product in use today is marijuana or Cannabis sativa. Indigenous to India and China, Cannabis has been the subject of increasing decriminalization worldwide due in part to its clinical, medicinal effects in multiple sclerosis, cancer, and AIDS.

Over the last few months, I’ve seen reports of a so-called “synthetic marijuana” being sold on the internet with stories most commonly coming from England and Germany and, in the US, from Kansas, Missouri, and Arizona. In fact, the St. Louis Post-Dispatch reports today that a bill has been brought before the Missouri House Public Safety Committee seeking to add this product to the state’s list of illegal drugs.

I became intrigued as to why anyone would go through the trouble of making a synthetic marijuana when the real thing is so readily cultivated worldwide, albeit illegally in most locales.

So what is it?

“Fake weed”
Synthetic marijuana, marketed as K2 or Spice, is an herbal substance sold as an incense or smoking material that remains legal in the United States. The products contain one or more synthetic compounds that behave similarly to the primary psychoactive constituent of marijuana, &Delta⁹-tetrahydrocannabinol or THC.

The compound most commonly found in these products is a chemical first synthesized by the well-known Clemson University organic chemist, Prof John W Huffman: the eponymous JWH-018. Another compound, found in Spice products sold in Germany, is an analog of CP-47,497, a cannabinoid developed by Pfizer over 20 years ago.
Known as (1-pentyl-3-(1-naphthoyl)indole), or the more proper IUPAC name of Naphthalen-1-yl-(1-pentylindol-3-yl)methanone, JWH-018 is one of over 100 indoles, pyrroles, and indenes synthesized by the Huffman laboratory to develop cannabimimetics, drugs that mimic the effect of cannabinoids such as THC. The primary goal of these studies was to create pharmacological probes to 1) determine the structure-activity relationships of these compounds and 2) tease out the physiological function of subtypes of receptors we have for cannabinoids: the CB1 and CB2 receptors.

What does it do?
Much of the biological assessment work of Dr. Huffman’s compounds was carried out by the laboratory of Professor Billy R. Martin of the Medical College of Virginia. Dr. Martin, a native of North Carolina, was a giant in the field and sadly left us two summers ago at the all-too-young age of 65 (obituary).

According to this 2000 paper in Drug and Alcohol Dependence from the Huffman and Martin groups, JWH-018 binds to the psychotropic CB1 receptor with approximately 4 times the potency of the naturally-occurring THC. Unlike THC, which binds with almost equal affinity to CB1 and CB2 receptors, JWH-018 exhibits a 3-fold preference for CB1 receptors.

What does this mean? Well, the CB1 receptor is the primary means by which cannabinoids exert their psychotropic effects. The CB2 receptor, on the other hand, appears to be more involved in pain and inflammation and is therefore a very active area of research for new therapeutics.

So while JWH-018 has four-fold greater potency for CB1 receptors than THC in an isolated receptor binding study, how its effect compares to plain-old marijuana depends on other factors such as the relative amount in the product, how stable it is to combustion, how it’s metabolized in the body, among others.

“We don’t know much about this, but it’s going to end up killing somebody”
I’m not going out on a limb to say that this statement of Missouri Rep. Ward Frantz might be a bit hysterical at this point but I could be wrong. Human toxicology studies have not been done and the indole moiety of the drug dose raise the possibility that it may cause serotonin syndrome, a potentially fatal but relatively rare disorder. Otherwise, this concern is far overblown when compared with other drug issues in America’s heartland such as methamphetamine.

“Surprised it took this long”
It’s worth reading the backstory on Professor Huffman in this UK Guardian/The Observer article:

JWH-018 was “nothing special”, Dr Huffman remembered, “but it was one of the more potent compounds we made, and it was quite easy to make from commercially available materials. Probably the reason it has now caught on.” […]

[…]”My biggest surprise was that this all hadn’t happened sooner,” he told me. “All it needed was somebody with a reasonable understanding of science to see the papers we had published and think, ‘Aha!'”

And with the perspective of a 77-year-old organic chemist:

“I’ve lived around the world a long time,” said Dr Huffman. “I’ve come to the conclusion that if an enterprising person wants to find a new way to get high, they’re going to do it.”

JWH-018 is however already classified as illegal in several European and Scandinavian countries. So unless JWH-018 does something different from garden-variety marijuana, outlawing it in the US will just push folks back to God’s own herb.

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Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, & Martin BR (2000). Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. Drug and Alcohol Dependence, 60 (2), 133-40 PMID: 10940540