The global prohibition of psychoactive drugs has arguably caused more suffering than it could ever prevent. A recent UN report shows that it also stimulates the creativity of those who create new designer drugs and ‘legal highs’. Neuroscientists have warned, on the other hand, that drugs control stifles research that could advance our understanding of the mind and find valuable therapies for mental disorders. Michael Gross reports.

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In August 1897, the chemist Felix Hoffmann created two new painkillers. The first, aspirin, had a lukewarm reception from his company at first, but the second one, a chemical modification of morphine, was soon produced in large quantities and promoted enthusiastically.

At the dawn of the 20th century, doctors prescribed it for nearly every illness under the sun, including depression, bronchitis, asthma, and coughs. Mountaineers used it in preparation for their climbing tours, and psychiatrists gave it to their patients. To honour Hoffmann’s heroic invention, Bayer called it heroin. Little did the company bosses know what the future held for their heroic product.

After 1910, morphine addicts in the US started switching to the new drug, in the 1920s the wave of misuse reached Europe, and by 1931 the control laws had been tightened so much that Hoffmann’s heroin was practically dead as a medical drug — much to the disadvantage of patients, as it really does have significant benefits as a strong painkiller.

So what went wrong and how could Bayer’s big hope turn into such a disaster? It was simply a question of how people use the drug. Patients can safely swallow a couple of milligrams, as there is no risk of getting addicted to it, and there is no rapturous high either. It is just a painkiller. Heroin junkies use around ten times more and they inject it, leading to a more dramatic effect, as the whole dose overwhelms the brain at once. Even then, clean heroin isn’t nearly as dangerous as the record of fatalities suggests. Most of the dangers of street heroin arise from impurities, deliberate stretching, and non-sterile needles.

Heroin, like many other inventions, is a dual-use technology. The molecule by itself is neither good nor bad, but it can be helpful or harmful depending on what people do with it, and also how authorities manage the use and misuse.

Losing the war on drugs Tight control laws based on three UN treaties from 1961, 1971 and 1988 have failed to curb the global demand and supply of drugs. Essentially, they have had two main effects on the drugs market: pushing the trade underground, and encouraging people to look for new kinds of drugs that enjoy a brief fame as ‘legal highs’ until they, too, get banned. In 2009, the magazine The Economist, quite far from any suspicions of hippie sympathies or dope-headedness, ran a major story on the 100th anniversary of the Shanghai Opium Commission (the first international conference on drugs) and concluded unequivocally that the global war on drugs is unwinnable. The incarceration of hundreds of thousands of young people who have committed no crime other than possessing cannabis, the unimaginably cruel gang wars along the smugglers’ route through Central America, the death sentences handed to alleged drug mules in Asian countries, and the unshakably constant levels of drugs supply and demand all suggest that prohibition is doing more harm than good. This conclusion shouldn’t surprise anyone who has considered the precedent of alcohol prohibition in the US from 1920 to 1933. Nevertheless, the most recent world drug report from the United Nations Office on Drugs and Crime (UNODC), published in June 2013, insists on carrying on as before, even though the figures within the report show that drug use has remained stable compared with the previous data from 2009. What has changed since 2009 is that the invention of new legal highs is now a booming business, to which roughly half of the length of the report is dedicated. The report finds that the number of new, still legal substances now exceeds the number of drugs banned under international drug treaties. The UNODC report bundles as ‘New Psychoactive Substances’ (NPS) all those that emerged onto the international market after the 1971 convention, even though some of them have been used for much longer. Heroic invention: The company Bayer had great hopes for its new painkiller, heroin, at the beginning of the 20th century. Within two decades, however, its dreams turned into a nightmare. (Photo: Wikimedia Commons.) Green shoots: The cannabis plant (Cannabis sativa) can look back on millennia of usefulness to mankind, from hemp fibres used in the Gutenberg bible through to medications given to Queen Victoria. Its criminalisation under global drug treaties induces people to try alternatives that aren’t banned yet, but may be more dangerous. (Photo: © GW Pharmaceuticals.) The report finds: “The emergence of new substances in the drug markets has clearly gained pace over the last decade: 251 NPS had been identified by Member States as of mid-2012.” By the time the report was released, this figure had risen to over 300. The product spectrum shifts quickly, both with fashion, and in response to attempts at blocking new substances. Current favourites include ‘Spice’ products (i.e. synthetic cannabinoids sprayed onto other herbs) and ‘bath salts’ containing synthetic cathinones (variants of the active ingredient of the khat plant). Synthetic cannabinoids alone accounted for a quarter of the substances reported, demonstrating that the market is driven by the desire to sidestep the prohibition of cannabis. “Most of these drugs act as stand-ins for MDMA (more commonly known as ecstasy), cannabis, LSD and mushrooms containing psilocybin (commonly known as magic mushrooms). The latter three drugs have no recorded cases of toxicological fatalities,” observes author Mike Power in a comment for The Guardian. Power, who has published a book on the internet drug trade (Drugs 2.0: The Web Revolution That’s Changing How the World Gets High), concludes that public health would be best served if the relatively safe substances like cannabis and magic mushrooms were legalised and put under official quality control. If people were allowed to smoke cannabis, there would be no demand for a confusing variety of new and untested cannabinoid products. Apart from newly synthesized substances, the NPS category also includes a few traditional plant-based materials with regional popularity, such as the herbal stimulant khat (also known as qat) in Yemen and the Horn of Africa. Several European countries have banned khat, but the UK government’s Advisory Council on the Misuse of Drugs (ACMD) published a review in February 2013 concluding that there was insufficient evidence of it causing any harm. Nevertheless, the home secretary Theresa May announced on July 3rd that the herb is going to be banned in the UK, ignoring the advice of the expert body. Former ACMD chair David Nutt ridiculed the decision in a comment for The Guardian newspaper published the same day, writing it would make just as much sense to ban cats. The UNODC report acknowledges that it is impractical to include an ever more rapidly growing number of new substances in new international control strategies, but doesn’t admit that prohibition itself is the root cause of this proliferation, as Power has pointed out. Several countries have introduced new control measures to respond quickly to new substances emerging. In the UK, the Netherlands and Germany, ministers can ban a substance for a year, to allow the legislator time to classify them. Similarly, the US has ordered preliminary scheduling for several synthetic cannabinoids and synthetic cathinones before putting them under permanent control regulations. Regarding the various attempts by some countries to put a lid on new substances, the report concludes: “While all of these approaches have pros and cons, they are all valuable experiments.” However, it also cautions that it is too early to see which, if any, of these individual approaches works.

Censoring neuroscience Apart from the futility and the human cost of drugs prohibition, there is a third reason to reconsider the policy. A growing number of neuroscientists argue that legal restrictions on mind-altering drugs are stopping them both from gaining a better understanding of the brain and from developing new therapies for mental disorders. In a recent paper, David Nutt from Imperial College, together with Leslie King, formerly at the UK’s Forensic Science Service, and David Nichols of the University of North Carolina argued this case in some detail (Nat. Rev. Neurosci. (2013) https://doi.org/10.1038/nrn3530 ). First, they reiterate the known flaws of the current drugs legislation. “The decisions that were made about which drugs should be controlled under this legislation seem to be unclear and inconsistent and may have been made for political rather than health-related reasons,” the authors write. In previous publications, Nutt and others had shown that there is little or no relation between the legal classification of substances and their actual danger. Nutt famously stated that in terms of fatalities per time spent on a recreational activity, horse riding is more dangerous than taking an ecstasy pill on a night out. Rather than adjusting the policy to the evidence, the then home secretary of the UK, Alan Johnson, responded by forcing Nutt to resign from his post as chairman of the ACMD in 2009. One argument often used in drug classification is the lack of medical use. However, the authors argue, “once a drug is classified under Schedule 1, it is unlikely that any medical value will ever be discovered for it, because it is extremely difficult to research the drug. The argument […] thus becomes circular.” The barriers preventing research on Schedule 1 drugs are significant. Each institution has to apply for a special licence to deal with such drugs, and install extra levels of security to prevent misuse. Even researchers handling minute amounts, less than a single dose a drug user would take, have to follow procedures to account for the whereabouts of that amount. In the UK, the authors say, there are only three hospitals that have this special licence and can handle cannabis or MDMA (ecstasy). Ironically, all UK hospitals are allowed to handle opioids, including heroin, which is only classified as Schedule 2 in the UK, even though its abuse is a much greater worry than that of cannabis or ecstasy. To make matters worse, funding agencies and ethics committees generally shy away from approving any research projects involving such drugs, on the false assumption that these must be very dangerous. Only a few organisations, typically those specialising on such issues, fund research with such drugs. These include the Beckley Foundation, the Heffter Research Institute, and the Multidisciplinary Association for Psychedelic Studies (MAPS). Nutt and colleagues argue that this situation severely inhibits progress in neuroscience. After all, it is no coincidence that these much-maligned substances have profound influence on the mind. They do so, because they interact with specific receptors that are important for our brain function, and thus studies of their mechanisms could reveal important details. For instance, cannabis has an effect on us because the body uses similar substances, the endocannabinoids, as molecular messengers. One class of endocannabinoid receptors, the authors say, is the most densely expressed group of G-protein coupled receptors in the human body. And yet, research papers on the function of these receptors are sparse because of the legal barriers inhibiting this research. One UK company, GW Pharmaceuticals, managed to bypass all these hurdles and obtain a licence for Sativex™, an alcoholic solution of THC and other cannabinoids, which can be prescribed for the treatment of pain and spasticity in multiple sclerosis. Even though this clearly demonstrates medical usefulness of cannabis, it did not lead to abolition of its Schedule 1 status. Pain relief: Sativex™ is a cannabis-based prescription drug developed by GW Pharmaceuticals in the UK and licensed for treatment of pain and spasticity in multiple sclerosis. (Photo: © GW Pharmaceuticals.) Similarly, there are known medical uses for MDMA (ecstasy), which was first used in the US to facilitate psychotherapy, as it enabled people to open up and communicate better. It was also found beneficial in a small clinical trial of patients with post-traumatic stress disorder. Specifically, MDMA makes it easier for patients to relive the trauma and thereby overcome it, which is part of the currently accepted therapy, but would in some very severe cases be unbearable for patients without the drug. Psychedelics, such as LSD, with their mind-altering activity have long been seen as immensely interesting scientific tools for the study of mind and consciousness. This was also the view of the discoverer of LSD, Albert Hofmann, who never saw his ‘problem child’ as a recreational drug. As he lived to the age of 102, his own experiments with his drug seem to have had no ill effect. In the 1950s and 60s, there was a vibrant research field studying the effects of LSD on the brain, which all but disappeared after the substance was banned. It was unfortunate timing that this ban struck it down before the emergence of brain imaging techniques that could have revealed what actually happens in a brain on an LSD trip. As the perceptions and consciousness of people under its influence are so drastically different from their sober selves, many scientists think that such research could have revealed quite a lot about the inner workings of our minds. In fundamental neuroscience, psychedelics are valuable as they are agonists of the serotonin receptor 5-HT 2A , which is highly expressed in a group of neurons in the cortex thought to be involved in top-down processing of sensations and emotions, and which may be affected in conditions including schizophrenia and depression. Since the paper appeared, Nutt says, “we have discovered the recent banning under a TBO [Temporary Banning Order] of many chemicals in the NBOMe series means the only PET [positron emission tomography] tracer for the agonist state of the 5HT receptor is now illegal!” The UK government banned the psychedelic NBOMe and the amphetamine-mimicking stimulant Benzo Fury with effect from June 10th for 12 months, while the ACMD prepares an assessment. Psychedelics are also of interest for clinical applications. LSD was investigated (before the ban) as a tool for psychotherapy as well as to treat alcohol addiction. After the ban, these clinical studies moved on to legal substances, such as psilocybin (from magic mushrooms), which in its turn was banned in the UK in 2005. Psychedelic molecule: Albert Hofmann, the inventor and first user of LSD, with a model of the molecule he called his ‘problem child’. Far from seeing it as a recreational drug, Hofmann hoped that it would enable people to gain a deeper understanding of consciousness and spirituality. (Photo: istockphoto.com.) Psychedelics have also shown promise for treatment of obsessive compulsive disorder (OCD) and of cluster headaches, a severe condition with few other treatment options and a significant suicide risk. “This hindering of research and therapy is motivated by politics, not science. It’s one of the most scandalous examples of scientific censorship in modern times,” said Nutt in a press statement.