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Shame on you, John!

The ethics of synthetic cannabinoid research

Philip Strange 31 January 2010

Grey area: what's in your herbal cigarette?

This sort of research is always going to attract attention and if you deliberately set out to make mimics of THC then you run the risk of creating new super drugs

When you see something that is technically sweet, you go ahead and do it and you argue about what to do about it only after you have had your technical success.

These are the words of Robert Oppenheimer reflecting on the development of the atomic bomb. Thankfully most of us do not end up having to wrestle with such weighty ethical issues. But how widely should ethical issues be considered when we plan a research project or start an experiment? There are obvious areas such as medical research where ethics must be stringently considered, but other more abstract subjects, such as organic chemistry, seem like they should be ethics-free zones. Yet imagine that we are organic chemists who make a new chemical as part of a curiosity-driven project. Someone else then follows our recipe, makes the same chemical and does bad things with it. Are we then responsible for what the bad people have done?

This issue surfaced recently on BBC Radio 4's Today programme when the host, John Humphrys, in full belligerent mode, interviewed Dr John Huffman, an organic chemist from Clemson University, South Carolina about a chemical he had synthesised in the mid 1990s. The chemical had subsequently been used as a cannabis substitute; on the day of the interview, it had become officially illegal in the UK.

Humphrys asked Huffman the unusual question: “Are you ashamed that you made it now it has been banned?”

“Not at all,” was Huffman’s reply.

Huffman’s chemical had been co-opted into a cannabis substitute called Spice, marketed under names such as Spice Gold, Spice Silver and Yucatan Fire. Spice first became available via the internet and in head shops in the early 2000s as a herbal mixture sold as incense but promoted as giving you a natural high if you smoked it. Unusually for these kinds of preparation, Spice actually did give users a high and eventually this lead to the investigation of its composition. It took until late 2008 for investigators to reveal its components: a mixture of innocuous plant materials laced with some synthetic cannabinoid-like drugs.

One of the main cannabinoid-like drugs that had been added to Spice is a compound called JWH-018, which was first synthesised in the lab of Dr Huffman in 1995 and shown to be a potent mimic of the endogenous principal of cannabis, tetrahydrocannabinol (THC). Huffman’s lab subsequently made many other compounds related to JWH-018 and quite a few of these also have THC-like activity. The compound JWH-018 remained a research curiosity until some clever soul, possibly in the Far East, had an idea – and what an audacious, intelligent and evil idea it was. They found that JWH-018 could be made easily, so they put together a herbal mixture that looked like cannabis and sprayed synthetic cannabinoids, including JWH-018, over it. The mixture was then marketed as “Spice”, but the packet declared only the herbal content and made no reference to the JWH-018. One can assume that whoever made the product knew that someone would try smoking it, and word of its interesting properties would then spread, most likely over the internet so that they would sell more and make lots of money. Sales would probably be good as the smoking mixture would be legal until the additives were discovered. To slow down discovery of the additives, they included a large amount of vitamin E, which would confuse analyses. (By the way, you can also get pure JWH-018 via the internet if you want to make your own smoking mixture. It is marketed as a 'Bonsai plant food'.)

This fascinating story raises many issues. Should Huffman feel any shame about his compound, as Humphrys insinuated? He produced it as part of a basic research programme to probe the structure of cannabinoid drugs and their receptors. There is no evidence that he has tried to market it or promote it, so I see no reason why he should feel shame. One of the other synthetic cannabinoids in Spice mixtures is CP 47,497 a compound originally synthesised by Pfizer, and I have not seen anyone accusing Pfizer of shameful behaviour. In my opinion, Humphrys actually missed a journalistic opportunity by focusing on Huffman rather than looking into who had put the Spice mixtures together, why had they been so successful and what the implications were of the events for future illicit drug use.

Meanwhile, the media interest has been a huge irritation for Huffman and has taken a lot of his time. I remember well, about twenty years ago, my Head of Department passing me a Scientific American article on cannabinoid receptors and saying, Philip, why don’t you work on something interesting? I'm not sure the price you pay is really worth it. This sort of research is always going to attract attention and if you deliberately set out to make mimics of THC then you run the risk of creating new super drugs. I am quite surprised that these compounds were not seen as a potential danger earlier by the regulatory authorities. Several of the compounds made by Huffman are more potent than THC itself and all the data have been published. The availability of cheap organic synthesis in the Far East, together with the internet, makes it all the easier to carry out such a scam.

But do we really need to worry about this? Do these compounds and the Spice mixtures pose any risks? There has been very little safety assessment of the compounds in terms of toxicology and teratogenicity. The psychoactive effects on humans have not been formally examined in detail, although there are worrying reports on the internet of intense fear reactions and panic attacks in some users; moreover, tolerance may develop. The purity of the compounds is unclear and the amounts of compound used in the Spice mixture are variable, so that anyone using the pure compounds or the Spice mixture is taking a big risk. On that basis, potential users need to be protected. Making the compounds illegal may have the effect of deterring some people from using these mixtures but we are no longer in a "back street” situation with supply. The internet allows knowledge about the drugs to circulate freely and provides a discrete way to sell them. Making these substances illegal is all very well but there needs to be intense education about the dangers of these untried, uncharacterised and potentially toxic compounds.

Huffman asserts that there is no medical application for these compounds, but is this a fair comment? There has been great interest in the development of cannabinoid-related drugs in the pharmaceutical industry and a few products are available. Synthetic cannabinoids related to JWH-018 might act as analgesics or appetite stimulants, but the psychoactive effects could be a problem. I wonder whether there could also be more sinister uses of the compounds. Cannabis has, in the past, been used as a “truth drug” with some success according to anecdotal reports. Another possible use could be as “calmative agents”. There is increasing concern about this new use of psychoactive compounds for control of groups of people. The JWH compounds might act in either of these more sinister ways.

But I'd like to end on a lighter note. In one of the analytical papers that detected synthetic cannabinoids in Spice mixtures, the components were extracted with solvent and analysed by gas chromatography and mass spectrophotometry. Before they did this, however, the paper informs us in wonderfully bland language that two of the researchers smoked the Spice mixture themselves to make sure it worked.

It did!