Synthetic marijuana, K2, Spice, JWH-018 and, you guessed it, dependence

When I first read Abel Pharmboy’s post introducing the notion of recreational use of a synthetic cannabinoid adulterated burnable product, my first thought was the US Controlled Substance Analogue Enforcement of 1986, aka the Federal Analog Act (Wikipedia). From the justice department page about analogues:

They are structurally or pharmacologically similar to Schedule I or II controlled substances and have no legitimate medical use. A substance which meets the definition of a controlled substance analogue and is intended for human consumption is treated under the CSA as if it were a controlled substance in Schedule I.

sourceAs Abel pointed out, these so called synthetic marijuana products are some variety of dried vegetable matter adulterated with one or more compounds that convey similar pharmacological properties as does Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana. Compounds which appear to be highly popular are the ones known as CP-47,497 and JWH-018.

The reason? Simple (Abel Pharmboy again):

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, JHW-018 exhibits a 3-fold preference for CB1 receptors.

Exactly. The CB1 receptor, of course, is where THC acts to produce the psychotropic effects. Okay so even if these compounds are sufficiently structurally distinct from THC to avoid triggering the structural similarity clause, they should trigger the pharmacological similarity clause, right? Apparently not. A Missouri state legislator has decided to introduce banning legislation because these synthetic marijuana products are currently legal. Why? Well, according to the Wikipedia entry:

Based on the case law it would appear that this section has so far been interpreted to mean that a substance must fulfill both parts A(i) and A(ii), i.e. it must have a structure substantially similar to that of a controlled drug, and produce pharmacological effects substantially similar to those of the controlled drug with which it is being compared, in order to be considered a controlled substance analogue. However this has not been conclusively decided and it is possible that the DEA might attempt a prosecution based on only one of these parts if they felt that it was appropriate, for instance if a new drug started being sold which had effects similar to an existing drug of abuse but which had no structural resemblance to any controlled drug.

At this point, many of my readers are going to echo Abel Pharmboy who observed in his post:

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.

Another way to express this is Problem? What problem?
We are, of course, very early in the recreational use cycle for this product. The lead indicators are, as always, the reports that are fascinating to me…and infuriating to a certain segment of my readership. Yes, Dear Reader, I have a Case Report for your consideration.
Withdrawal phenomena and dependence syndrome after the consumption of “spice gold”. Zimmermann US, Winkelmann PR, Pilhatsch M, Nees JA, Spanagel R, Schulz K. Dtsch Arztebl Int. 2009 Jul;106(27):464-7. Epub 2009 Jul 3.
No fear, it is available at PubMed Central here and yes, it is in English. So you can read it yourself to dispute my description if you like.
The report describes a 20 yr old man with a little prior experience with hashish, some hallucinogens, minimal alcohol consumption and about 10 cigarettes per day. No other illicit drugs reported, nor detected in blood tests during the clinical care interval.
His primary drug problem was with “Spice Gold” a synthetic marijuana product the case authors apparently procured, had two volunteers confirm a cannabis-typical psychoactive effect* and ruled out any THC related structures via mass spec. It is a little uncertain here but they are relying on this article reporting analysis of related products in concluding that, as Abel mentioned, CP-47,497 and JWH-018 are top suspects. So ticking off the interesting symptoms:

he has only been consuming “Spice Gold,” initially 1 g daily, for eight months. Due to decreasing effect, he had rapidly increased the dose to a final value of 3 g daily–split into 3 to 4 doses, with the first dose early in the morning.
…
Owing to the consumption of the substance, he had often recently been listless and had had problems in thinking clearly

Check and check. Referring to DSM-IV diagnostic criteria, we have tolerance, use despite physical / psychological problem (see below) and perhaps interference with major role responsibilities.

A few weeks ago during a phase of abstinence owing to shortages in supply, he had developed symptoms in the form of profuse sweating during the day and especially in the night, as well as internal unrest, tremor, palpitation, insomnia, headache, diarrhea, nausea, and vomiting. Additionally he had suddenly felt depressed and desperate.

Ahh, yes. Sounds like a withdrawal. Is it substance-typical? Yep, sure sounds like it.

This had lasted for two days and had only abruptly disappeared after taking the drug again. Therefore, he no longer had the courage to discontinue the drug by himself.

Yep, taking drug to avoid the withdrawal is another diagnostic criterion.
The report goes on to detail the days of inpatient detoxification of the patient. You can read those symptoms and then look at the literature on cannabis withdrawal here, here, here and here for starters.
My read is that the symptoms reported in this case report are entirely consistent with cannabis dependence.
This is entirely unsurprising to us in the field, I realize. We have potent CB1 compounds and humans using the product recreationally as a legal alternative to marijuana. Assuming that Abel’s concerns about bioavailability are unwarranted and this is not mere placebo effect, the risk of dependence is clearly indicated. This case report is one of the lead indicators. Will we see a continued trickle of case reports of dependence on this stuff? Sure, just so long as it remains available and consumed.
The interesting thing will be to see how long it take regulatory authorities to criminalize these so-called synthetic marijuana products in various jurisdictions. Availability and cost relative to good old marijuana will dictate whether this becomes a continuing issue for public health or not.
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*my source for the image performed a similar small-scale user test. The results appear to confirm subjective effects similar to marijuana. Since these are legal products in at least some jurisdictions where my readers reside, perhaps we will get some additional testimonials in the comments?