Methylenedioxymethamphetamine Ecstasy synthetic highs

Synthetic highs: redesigning the drug trade

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Fifty years after Timothy Leary exhorted a generation to ‘Turn on, tune in, drop out’, a growing trade in synthetic psychoactive drugs has begun to influence a new crowd of users, despite recent changes in UK drug laws.

This summer, you might have found John Ramsey searching drug amnesty bins at Glastonbury looking for new psychoactive substances (NPS). Once called ‘legal highs’, they are now illegal across the UK under the 2016 Psychoactive Substances Act.

Ramsey runs TICTAC Communications, a leading drug identification and information service based at St George’s, University of London. “We used to purchase them from websites and analyse them to find out what they were, but a consequence of the act has been to close all those sites so they are not as easy to find,” he explains.

Yet the new law does not mean that these drugs are going away. Marketing its products on the dark or deep internet and making use of the academic literature on psychoactive molecules, this new, synthetic version of the recreational drugs business is providing novel drugs for the curious or cheaper versions of established drugs for the vulnerable.

NPS have gained a lot of tabloid attention, but UK deaths involving NPS are low in comparison to opiate-caused deaths (1.9 deaths per million compared to 21.3). Deaths have increased though: from 82 in 2014, to 114 in 2015. “Today, the supply of NPS is still very wide and very diverse. There are still a large number of them being brought onto the market,” says Ana Gallegos of the Lisbon-based European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). The centre monitors more than 560 NPS and says around two additional substances are detected every week.

Over the last decade, this chemical churn has been partly attributable to an arms race between producers and legal authorities – once a molecule was banned, the chemists would design a slightly different alternative that bypassed the law, until that was also banned. The 2016 act stops this by outlawing ‘any substance that produces a psychoactive effect’ – a statement so broad that former chief government drugs adviser David Nutt called it “arguably the worst piece of legislation in living memory.” Yet it has closed the so-called high-street ‘head shops’ and UK-based internet sales.

The whole business model for NPS can be traced back to music entrepreneur Matt Bowden, in late 1990s New Zealand. Ramsey explains: “He had a drug problem and couldn’t easily get methamphetamine, the drug he wanted, but he had a friend who said there are other chemicals, why don’t you try those. He found one called benzylpiperazine (BZP), which worked and then - being an entrepreneur - he started selling it.” BZP was originally synthesised by Wellcome Research Labs in the 1970s as both an anti-parasitic and antidepressant, but it never reached clinical trials.

The model spawned a whole new drugs trade, with NPS rediscovered from scientific literature sold online, sometimes labelled as ‘research chemicals’ and ‘not for human consumption’, but clearly designed as recreational drugs. “People were looking at the chemical structures and thinking of what they could make in terms of analogues and producing it in a chemistry lab,” says Andrew Westwell, medicinal chemist at Cardiff University and co-founder of WEDINOS, a Welsh government-funded project that analyses difficult-to-identify NPS samples. Classifying new compounds often requires nuclear magnetic resonance spectroscopy, which isn’t available in toxicology labs. “There have been very few we have been unable to figure out because the structures are not that difficult,” says Westwell, “the substances we have analysed are often very high purity.”

Once synthesised, the NPS are tested and then reviewed in online drug forums with descriptions of their effects. Testers and early adopters are known as ‘psychonauts’ and the drugs whose effects they recommend are likely to get taken up by the market, while the less enjoyable ones fall away. Otherwise, these chemicals have had no safety testing. “It’s amazing that people will use completely untested chemicals – pharmaceutical companies spend five years and millions of dollars testing stuff before they give it to any patients,” Ramsey muses.

The other important facet of business is the bulk manufacture. The EMCDDA collects data on law-enforcement drug seizures and Gallegos says that “in many cases the country of origin is China”. While European chemists may design or commission the drugs, bulk manufacture happens elsewhere. China has started to acknowledge the problem and in 2015 brought over 100 NPS under control. Several media reports described raids on ‘chemical warehouses’ with huge underground labs, as well as reports of several chemistry professors arrested for manufacturing NPS. One was caught as he attempted to mail the drug methylone to clients in the West via standard postal services.

Amateurs have been ‘cooking up’ drugs like methamphetamine (crystal meth) for years, but designing an NPS is slightly different. “What people are doing is what we do as medicinal chemists – change the structure a little bit and see what happens,” explains Westwell. “You might say let’s put a chloro group in this position on the [benzene] ring or a methyl group.” With small changes, the new compounds are likely to still hit the same brain receptors that cause the psychoactivity, although outcomes aren’t guaranteed.

Do you need to be a Walter White, or could a Jesse Pinkman do it? “The chemistry is really not very complicated,” according to Westwell, “anyone with reasonable access to a lab and undergraduate knowledge of chemistry could produce these substances in pretty pure forms.”

Suzanne Fergus, a University of Hertfordshire chemist and NPS researcher, gives them a little more credit. “I imagine the chemists behind the design of new chemicals have a level of experience beyond this,” she says, which may be the case for those running commercial laboratories in China.

The key information comes from pharmaceutical research. As Fergus puts it: “Clandestine chemists using the internet have profited from failed patents.” Today’s designers have gone back in history to some of the pioneers of psychoactive compounds. Perhaps the most famous is Alexander Shulgin, the ‘godfather of psychedelics’, who died in 2014. Originally a research chemist, his interest stemmed from experiences with the psychedelic drug mescaline, derived from the Peyote cactus.

From the late 1960s, he independently researched psycho-pharmacology in a small synthetic laboratory behind his California house. Shulgin synthesised and tested effects of psychoactives including MDMA (methylenedioxymethamphetamine), the recreational drug Ecstasy. MDMA was first synthesised by pharmaceutical company Merck in 1912 as a clotting agent and used by the US military for interrogation studies in the 1950s. Shulgin tested hundreds of the drugs he synthesised, mainly analogues of phenethylamines (the family containing MDMA), and tryptamines (the family containing LSD), and in the 1990s published manuals describing their synthesis and psychoactive effects (which led to a law-enforcement raid on his lab).

As popularity of NPS grew, scientific literature on psychoactives from chemists such as Shulgin began to be discussed online, including methylone (methylenedioxymethcathinone or MDMC) a molecule patented by Shulgin in 1996 as an antidepressant and Parkinson’s disease drug. Classes of drugs such as cathinones had been investigated in pharmaceutical research but, due to their potential for addiction, most weren’t developed.

The herbal stimulant khat, widely chewed in Eastern Africa and parts of Arabia, contains cathinone, but of the synthetic versions, the most well-known is mephedrone (4-methylmethcathinone, 4-MMC or M-cat), which first emerged around 2007, sold as ‘plant food’. Its synthesis was described in 1929 in the Bulletin de la Société Chimique de France, under the name toluyl-alpha-monomethylaminoethylcetone, but was rediscovered in 2003 by Israeli underground mathematician/chemist ‘Kinetic’, now identifying as ‘Dr Zee’.

Perhaps illustrative of how drug-trends develop, the compound only grew in popularity in 2009 when there was a shortage of Ecstasy after a seizure in Cambodia of 33 tonnes of its key precursor chemical Safrole. Since then, new second-generation synthetic cathinones (in the US sometimes known as ‘bath salts’) are constantly appearing. A drug known as Flakka (a-Pyrrolidinopentiophenone – alpha-PVP) has recently been linked to bizarre ‘zombie-like’ behaviour and deaths.

Use of pharmaceutical research to develop dangerous recreational drugs has not been lost on researchers. David Nichols, chemistry professor at Purdue University in Indiana for 38 years, until retiring in 2012, carried out basic neuropharmacological research on serotonin and dopamine receptors and patented the method used to make amphetamines analogues. His papers were eventually used to synthesise Ecstasy substitutes – notably the drug methylthioamphetamine (MTA). Known as ‘flatliners’, it led to some deaths and, in recent years, Nichols acknowledged this. In a 2011 Nature article he said: “It left me with a hollow and depressed feeling for some time.” He admitted that he had subsequently decided not to publish information on a molecule he thought too toxic.

The biggest worry for many experts is the synthetic cannabinoids. “They are very potent, they can have very long-acting effects, act on multiple [brain] receptors and can cause absolute chaos,” says Ramsey of TICTAC Communications. “Most cannabis users prefer to use the real thing,” he adds, but they are popular with homeless people, because they are cheaper than cannabis, and the prison population, because they are not detected in standard drug tests. Deaths are still low (eight deaths in 2015) but increasing, and dangers have recently been highlighted by a cluster of incidents in Lancashire involving the synthetic cannabinoid ‘Spice’.

Synthetic cannabinoids also trace their history to pharmaceutical literature. In 1984, chemist John Huffman from Clemson University in South Carolina began developing cannabinoid compounds for multiple sclerosis, HIV/AIDS and chemotherapy drugs. Over the next 20 years, Huffman and his team developed 450 cannabinoids, as part of their research into the newly discovered cannabinoid receptors in the brain and other organs. By the late 2000s, two of Huffman’s compounds were sold as cannabis alternatives, under the names K2 and Spice. Now hundreds of different derivatives are available, including AB-FUBINACA, a defunct painkiller originally designed by pharmaceutical giant Pfizer in 2009.

Gallego explains that synthetic cannabinoids can be so dangerous as their appearance is likened to herbal drugs: “What producers do is they mix the powder with solvent and spray the solution onto herbal material to act as a support, so if you ask [a user], are you using a synthetic cannabinoid, some will say, no I am smoking the natural stuff.” Yet they are often much more potent and delivered at a higher level of purity, which increases risk of overdosing. Gallego says last summer a synthetic cannabinoid called MDMB-CHMICA started to appear: “One gram of the substance in pure powder form could give 1,000 doses – that gives you an indication that it is very potent.”

A recent trend has been the appearance of the opiate Fentanyl, the drug linked to the death of singer Prince. “Fentanyl is a very potent anaesthetic and we are seeing substances which have structures that are variations of Fentanyl but which are much more potent,” says Gallegos. This year has seen a spate of overdose deaths in Yorkshire and Cleveland, where heroin has been sold laced with Fentanyl. 

As well as potency, a change in chemical formula will also alter the pharmacokinetics – how long it takes the drug to get to the brain and how long it stays in the body. One of the first NPS analysed by Cardiff University’s Westwell was methoxetamine, which is an analogue of the animal tranquiliser ketamine. “I got a call one day a few years ago from an A&E doctor in Abergavenny [South Wales] who had a patient in a bad way, who had overdosed on this substance.” Westwell explains that “simple substitution of a hydrogen for a methoxy group retains psychoactive properties, but it meant it had a slower onset of activity, which is why this guy overdosed. People take a little and expect something to happen and if it doesn’t, they take more.”

By December 2016 the government reported 500 arrests and the first convictions secured under the new law, which came into force in May 2016. “Closing the shops has denied access of a lot of these things to vulnerable kids – that’s a good thing,” says Ramsey. Yet it may be too early to tell the overall effect on NPS use in the UK.

“I don’t think changing the law is going to make any difference to growth of the market,” says Westwell. “It will just change the means by which people access these substances.” Driven onto hidden parts of the internet, NPS are likely to be sold with other illegal drugs. “In a way it makes things more dangerous from a harm reduction perspective,” he adds.

The rise of NPS is also illustrative of another recent trend – a shift from recreational drug use to lifestyle use. “The internet has made substances more available to a group of users who don’t necessarily perceive themselves as drug users in the traditional sense,” explains Ornella Corazza, an addiction expert at the University of Hertfordshire. A form of ‘self-medication’ has developed, with substances available for fitness, weight loss, and even tanning. For example, Melanotan, a synthetic hormone analogue developed at the University of Arizona in the early 2000s, is sold for its tanning and aphrodisiac effects. “They perceive these substances are less harmful than traditional drugs,” adds Corazza, but as in any unregulated market, you do not know what you are getting.

It isn’t a coincidence that the NPS phenomenon developed in the internet and social networking era, where technical information is easy to track down and products simple to market. New laws may be able to disrupt parts of the new business model, but ultimately as long as they continue to make money for their purveyors, NPS are unlikely to go away.

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