NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By Donald L. Frederick, PhD, DABFT, FACB

Although K2 has been known since 1856 as the second highest mountain (to Everest) in the Karakorum Range, more recently K2 has been known for another type of high;  the high that is achieved by smoking synthetic cannabinoids.  Although the origin of these compounds can be traced to synthetic products produced over the last 40 years, the recreational use (abuse) has been more recent with the first internet sales occurring some time around 2006.  The majority of marketing and sale has been around a series of products identified as “Spice”.  There were some seizures of compounds in Europe in 2007 with subsequent analysis and identification of the active compounds in 2008. 

Some of the first identifications were of synthetic cannabinoids that belong to a class of naphthoylindoles that were synthesized by J.W. Hoffman as cannabinoid receptor agonists.  These were given the series name of JWH-xxx with the most common identified as JWH-018. These compounds have a higher degree of binding to the CB-1 receptor causing these compounds to exert more psychological response per weight than marijuana.  The other series of compounds found were the HU-xxx series from Hebrew University with some of the series like HU-210 having 100 times the potency of THC.  The third set of compounds are of the class CP-xx,xxx based on cyclohexylphenol developed by Pfizer in the 1970’s.  From analysis of “Spice” samples from Europe the JWH series is more common.

Until recently these compounds were legal to possess and use.  The DEA on November 24, 2010 published intent to regulate many of these compounds.  Other countries have also placed these compounds under regulation. 

The toxicology of the Spice mixtures is complicated for several reasons.  The plant material that is used is not consistent from one batch to the next making evaluation of the toxicity difficult.  Some of the plant materials have some physiological effects by themselves. The more difficult evaluation is the toxicity of this new range of compounds that do not have any significant toxicology research.  Additionally the “Spice” product does not just contain one synthetic cannabinoid but usually several from different classes such as JWH-018 together with CP 47,497.  Recent reports that deaths have occurred from the use of “Spice” alone suggests that the toxicity may be greater than initially suspected.

Testing for the presence of these compounds is very difficult analytically for several reasons.  Since the compounds are very potent, they are found at low concentrations and very little is know about the metabolism of these compounds with most metabolites not being available to validate any testing method.  A second reason is that the compounds are continuing to change.  If the regulators put one compound under control the producers can modify the compound slightly and produce another synthetic compound that will be a CB1 agonist.  Some testing laboratories have taken a new approach by looking for a pattern of compounds present that would suggest the specimen contained an array of synthetic cannabinoid.  The analytical work is challenging and is in the early days.


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Posted by
On 3/10/2011

In this issue (as in most other ones) we have to stick with our goals and not mix targets: (1)What was the question: Human risk assessment of these substances or analytical goals (for further studies)? (2) As in most drug (of abuse) related issues we should not let us be carried away by emotional statements! Indeed, these group of substances are being far from healthy, nevertheless for risk assessment one has to stay objective. A look onto the scene of (potential) users and on the market mechanisms tells us the situation is complex but by far not so confusing as described: We are dealing with derivatives of about 7 main classes of substances (1) Naphthoyl-Indoles, (2) Naphthylmethyl-Indoles, (3) Naphthoyl-Pyrroles, (4) Naphthylmethyl-Indenes, (5) Phenylacetyl-Indoles, (6) Cyclohexyl-Phenoles and (7) ‚Classic‘ Cannabinoides (Dibenzopyranes) which cover the majority of the CB1 receptor agonist known today! This is still is a huge analytical task (because of the large number of derivatives), but nevertheless all members the different groups carry structure specific properties! (3) There is a further important aspect: Most of the members of these groups have been characterized pharmacologically on their activity on the CB1 receptor: So why should be exspect (look) in a sample for members which show NO or LITTLE binding affintiy for the CB1 receptor??? It is irrational to sell a 'product' containing one of these inactive members, because they would display any (positive) effect (for the drug consumer). Such assumptions will reduce the number of potential candidates significantly. By additionally focusing first onto these substances with the highest receptor binding capacity (all listed in the scientific literature!), alleviates the problem further. (4) Considering all the potential metabolites is a secondary problem (for the time being) and should be reserved for a later detailed health risk assessment! kilian (Europe)

Posted by
On 3/10/2011

As I understand, these new compounds that are synthetic cannabiniods do not give a positive result when tested by urine screening test for cannabinoid. Is it possible to develop a urine drug test that uses the CB receptors to screen for the presence of these new products being sold? A test based on their ability to bind to the CB receptor may circumvent the ability to simply change to a new synthetic derivative. This comment was approved by the NACBLOG editorial board. Please remember to add your name and affiliation!

About the Author
Donald L. Frederick, PhD, DABFT, FACB
Donald L. Frederick, PhD, DABFT, FACB 

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Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: temporary placement of five synthetic cannabinoids into schedule I.  Fed Regist 2010;75:71635-8.

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