Source: New Scientist
Date: 29 September 2006

Legal highs on the rise

Lying back, exhaling: usually the last thing a person does before leaving this world. Only in this case it is the world that is leaving me.

A few minutes ago I smoked a pipe of Salvia divinorum, a powerful hallucinogenic herb that I bought openly and legally from a shop near my home. Of the £25 I handed over, more than £4 will find its way into government coffers in the form of sales tax. And salvia was just one of dozens of powerful but entirely legal psychoactive substances that I could have chosen.

All that was far from my mind as the salvia took me on a consciousness-expanding journey unlike any other I have ever experienced. My body felt disconnected from "me" and objects and people appeared cartoonish, surreal and marvellous. Then, as suddenly as it had began, it was over. The visions vanished and I was back in my bedroom. I spoke to my "sitter" - the friend who was watching over me, as recommended on the packaging - but my mouth was awkward and clumsy. When I attempted to stand my coordination was off. Within a couple of minutes, however, I was fine and clear-headed, though dripping with sweat. The whole experience had lasted less than 5 minutes.

My salvia trip was part of a journey into the world of "legal highs", a new generation of powerful mind-altering substances that are growing in popularity across the world. Accurate figures are hard to come by, as these substances are rarely monitored by drug-enforcement agencies. But the proliferation of online and high-street retailers suggest they are an increasingly lucrative business, and one company specialising in legal drugs recently reported an annual turnover of $16 million.

The reasons for their rising popularity are not hard to fathom. Not only are they legal and openly available in many countries, they work. Whether or not they are a good thing, however, is more difficult to decide. Supporters argue that legal highs are a bit of fun with a social conscience - a harm-reduction measure that allows people to experiment safely with psychoactive substances while separating drug use from criminality. Others say no one should be allowed to take such powerful drugs: the risks are too great. Some of the disagreement is down to the dearth of information about the short and long-term health effects of most of these substances, their potential for abuse and their addictiveness. But legal highs are also a battleground between those who see the use of mind-altering drugs as a human right and those who think it is plain wrong.

Faced with growing use and an information vacuum, governments are playing catch-up. Some, notably the US and Australia, are clamping down on each new substance as soon as they encounter it. Some are doing nothing. Others are commissioning research into the drugs and their effects before deciding what action to take.

And this is just the beginning. With hundreds of synthetic drugs on their way, not to mention traditional herbs that are being introduced to western consumers for the first time, some believe that cheap, easily available, legal highs could render the street drugs market redundant. So what do we know - and not know - about legal drugs?

Legal highs are nothing new. Paul Anand, manager of Shiva, the shop in Greenwich, London, where I bought my salvia, has been selling them for 15 years, starting with a stall at the Glastonbury festival. "Back then, I was selling guarana, damiana and wild lettuce," he says, "basically poor imitators of cannabis." There was a small market for the stuff, but among experienced drug users they were regarded as a joke, with few discernable effects.

That all changed with the arrival of new, reliable and effective substances, beginning in the UK at least with magic mushrooms. At the end of the 1990s, vendors started taking advantage of a legal loophole that permitted the sale of fresh mushrooms as long as they were not prepared in any way. Business boomed. In the year to April 2004 the number of shops selling magic mushrooms in England and Wales rose from a handful to over 400, according to the British Crime Survey. In the same period 260,000 people bought mushrooms - an increase of 40 per cent on the previous 12 months.

In July 2005, the government closed the loophole, outlawing the sale of fresh mushrooms containing the hallucinogens psilocybin and psilocin, but by then it was too late. The demand for legal highs had been established, and high street and internet vendors rushed to fill the void with an assortment of alternatives. These include another type of magic mushroom, the fly agaric (Amanita muscaria), which does not contain psilocybin or psilocin but is packed with other hallucinogens including muscimol. Salvia is another. And then there is an astonishing assortment of psychoactive herbs, pills and potions designed to mimic the effect of pretty much every illegal drug going.

No dodgy dealers

Inside the shop, the cornucopia of offerings cannot be exaggerated. Vials and bottles crammed with herbal extracts, tinctures, seeds and powders jostle for attention with packets of "party pills". There are hallucinogens, relaxants, aphrodisiacs, trippy highs, "loved-up" pills and euphorics. All entirely legal, at least in the UK. “There are hallucinogens, relaxants, aphrodisiacs, trippy highs, 'loved-up' pills and euphorics. All entirely legal”So why the sudden explosion? Anand says that his customers are attracted by the safety and quality of his products. "People are confident in what they're buying - that it's not cut with rat poison. They enjoy coming into the shop. They're not forced to meet a dodgy git in a UV-lit disco to buy an aspirin."

Vendors also make a selling point of legality. With drug testing increasingly routine at workplaces, 30 and 40-somethings are switching to highs that don't put them on the wrong side of the law, Anand says. And with legality comes, if not official approval, then at least an imprimatur of safety.

The majority of Anand's customers are aged between 20 and 30, he says. Most have tried street drugs and are now looking for something safer, more reliable, legal and affordable. And they're part of a growing movement: one leading vendor of legal highs, Stargate of Auckland, New Zealand, recently reported an annual turnover of NZ$24 million (approximately US$16 million).

Among the most popular legal highs are "party pills" made from compounds called piperazines, which are chemically similar to Viagra but with an amphetamine-like action. Known by various brand names such as PEP and Bliss, their main active ingredient is BZP (benzylpiperazine) - the "Z" pronounced US-style to rhyme with the "B". Originally developed as a drug to treat parasites in livestock, piperazines have been sporadically used on the dance scene for many years but began to seriously take off about three years ago - though not in the US, where they have been strictly illegal since 2002. Anand started selling them in January 2006 and says that every month they grow more popular.

The BZP story started in the late 1990s, when the drug was "discovered" by New Zealand entrepreneur Matt Bowden. The former musician and recreational drug user became hooked on illegal amphetamines in the 1990s during an epidemic of methamphetamine - "crystal meth" - addiction that swept the country. He had already lost a family member to ecstasy when, in the mid-1990s, he witnessed a friend on meth commit a horrific suicide - disembowelling himself with a samurai sword - at a party.

Bowden became determined to kick the habit. His efforts to quit led him to experiment with legal alternatives and he sought out a professor of neuropharmacology to tutor him and work alongside him on the project.

"I said, let's find something which is like methamphetamine but non-addictive and has an extremely low risk of overdose or death," Bowden says. They searched through the scientific literature and came across a piperazine which occasionally cropped up as an ecstasy alternative called A2.

"We looked at a US study and found that one part of the molecule caused liver damage in rats, but the other part appeared to be perfectly safe. That part was BZP," he says.

In 2000, Bowden used the compound to break his addiction to methamphetamine and then began giving it out for free to friends. By 2002, companies had begun making and selling BZP. The move led Bowden to set up his own company, Stargate, to market safe, legal alternatives to street drugs.

Stargate now produces and sells a range of pills based on piperazine blends. BZP is often combined with another piperazine, TFMPP (trifluorophenylmethylpiperazine), which gives the pills a relaxing, euphoric effect that has been compared to ecstasy.

Both drugs activate the 5HT serotonin receptor in the brain - the same receptor targeted by amphetamines and MDMA - and cause the release of dopamine (Neuropsychopharmacology, vol 30, p 550). This is responsible for the "high" associated with the pills, though it can also lead to anxiety, overheating and dehydration. In one survey, only half of people who had used BZP said they would describe its effects as "good"; 16 per cent said it was "good early but bad later", 10 per cent "bad" and 14 per cent "neither good nor bad". My own experience of using BZP was mixed, with some enjoyable effects but also a bout of paranoia, insomnia and a bad hangover the next day.

Worldwide, Bowden sells a million pills a year and, all told, New Zealand's legal party pills industry is worth around NZ$50 million a year. As these figures suggest, a lot of New Zealanders take BZP. In June, researchers at Massey University in Auckland released the results of a survey of more than 2000 people, commissioned by the New Zealand government. "We expected that no more than 5 per cent of those questioned would have tried BZP, but we actually found that 20 per cent of people had tried the drug, and 1 in 7 of 15 to 45-year-olds had used BZP in the past year," says study leader Chris Wilkins.

Wilkins says that the highest usage was by those in their 20s, as he had expected, but he also discovered high levels of use by people in their 30s and 40s.

A separate survey of around 1000 people carried out in Hamilton, New Zealand's seventh-largest city, yielded similar figures. It found that 12 per cent of the city's total population, and 30 per cent of 14 to 25-year-olds, had taken BZP at some point (Emergency Medicine Australasia, vol 18, p 180).

The popularity of BZP, along with anecdotal reports of adverse reactions, withdrawal symptoms and psychotic episodes, has led some politicians and doctors to start campaigning for a ban. Bowden, however, argues that his products are "harmless fun" and actually reduce demand for street drugs and the damage they cause; the pills are even labelled as "drug-harm minimisation solutions". He and other vendors have an agreement to sell them only to adults and in outlets where alcohol is not available.

"If we accept that people have the right to experiment with their minds, just as they try paragliding or drag racing, then it is the responsibility of governments to ensure that they have access to well-designed drugs," Bowden says.

There is some evidence in support of Bowden's argument that BZP reduces the demand for street drugs. In the Hamilton survey, 44 per cent of the 15 to 45-year-olds who had tried BZP said they had stopped taking illegal drugs as a result. In 2005, the head of the New Plymouth Criminal Investigation Branch, Grant Coward, said that the use of ecstasy had dropped after BZP became available. It also appears that the relatively low price of BZP diverts people away from illegal drugs. An ecstasy pill in New Zealand costs up to NZ$80; the same amount will buy you up to 12 BZP tablets. "Most users said that they would rather take ecstasy than BZP because the effect is preferable and the hangover not as bad, but they're priced out of it," Wilkins says. What is not clear, however, is whether BZP acts as a gateway to illegal drugs among people who would otherwise never have taken them.

Wilkins also points out that the drug seems to have less abuse potential than amphetamines. "It gives you quite a bad hangover, so people tend to limit their usage of it," he says. Overall, however, Wilkins says it is too early to conclude that BZP reduces harm.

Health worries

Worries are also emerging about the health effects of the drug. According to emergency doctor Paul Gee from Christchurch Hospital, BZP-related admissions were almost unheard of two years ago but are now commonplace. Between April and September 2005, his team dealt with 80 users complaining of nausea, vomiting, anxiety and palpitations. Some had seizures; two cases were life-threatening (The New Zealand Medical Journal, vol 118, p U1784). And while there have been no deaths directly attributed to BZP, in 2001 a woman died in Zurich after taking it with MDMA.

One of the biggest worries is that, because BZP is advertised as a "safer alternative", it fosters the belief that it is completely harmless and encourages people to take more than the recommended dose (about 200 milligrams). In the Hamilton survey, around a third of 14 to 25-year-olds who had taken BZP said they did not read the instructions on the packaging. Nearly half took more than the recommended number of pills, and 66 per cent drank alcohol at the same time, which is not advisable as alcohol exacerbates the dehydrating effects of BZP.

The non-addictiveness and limited abuse potential of BZP have also been called into question with a study showing that rhesus monkeys will intravenously self-administer the drug at rates as high as they would for cocaine (Drug and Alcohol Dependence, vol 77, p 161). What's more, work due to be published in the journal Neurotoxicology and Teratology shows that adolescent rats given BZP grow up into anxious adults.

With the doubts about BZP growing, it is no surprise that governments are sitting up and taking notice. In 2002 the US temporarily placed the drug on its schedule 1 rating, the same category as MDMA and heroin, and confirmed this in 2004. BZP has recently been made illegal in Japan, Denmark, Greece, Sweden and, as of 1 September, Australia. In the UK, BZP remains legal but is on the agenda for discussion at the government's advisory council on the misuse of drugs meeting on 2 November, where a decision will be taken as to whether BZP needs to be monitored further.

New Zealand, however, has taken a different and arguably more enlightened approach. In 2001 Bowden approached the government to ask for its help in regulating the new industry. In response the government introduced a new class of drug called "non-traditional designer substances", also known as class D. This class is a repository for new and little-researched drugs, such as BZP, pending further information. Class D drugs are legal, though there are some restrictions on them; in BZP's case that means a ban on sales to under-18s and in places that sell alcohol.

The government also commissioned three studies into BZP. One, the Hamilton prevalence study, has already been published. The other two concern the drug's health effects and are due out in November; Wilkins expects both to be critical. The outcome of these studies will heavily influence the legal status of BZP in New Zealand.

Whatever the fate of BZP, party pills won't be the last legal high to occupy government time. Thanks to the efforts of Bowden and like-minded individuals, new psychoactive substances - both natural and synthetic - continue to enter the market.

The next craze is likely to be for a legal high called kratom. This extract of a tree native to south-east Asia has been dubbed the "herbal speedball" for its euphoric and energising properties. Kratom's main active ingredient, mitragynine, binds to the same opiate receptor (mu) as opium, heroin and cocaine. There are no documented overdoses or fatalities and proponents claim it is non-addictive, although last year a team from Josai International University in Togane, Japan, published evidence to the contrary (Life Sciences, vol 78, p 2). It is legal almost everywhere except Thailand and Australia. In high doses it is supposed to produce hallucinogenic effects. However, when I tried it - boiling the leaves to make a nauseating tea - it merely made me sick and sleepy.

According to a US National Drug Intelligence Center report published in 2005, kratom is cheap and widely available in the US and has "high abuse potential", though up to now there have been no moves to ban it. That is sure to change. Arguably, drugs such as kratom are legal not because they have official approval but by default: they have yet to become popular enough to attract the attention of lawmakers. Once that happens - as with magic mushrooms in the UK - governments are quick to clamp down.

Another high that appears to be on the brink of losing its legal status is salvia. Also known as diviner's sage, "magic mint" or "Sally D", Salvia divinorum is a white-and-blue-flowered sage plant that grows in the Oaxaca mountains in Mexico. It has been used for centuries by the Mazatec people in shamanistic rituals and in healing.

The first westerner to experience salvia's powerful hallucinogenic effects was anthropologist Brett Blosser, now of Humboldt State University in Arcata, California. In the late 1980s, he was invited to take part in a Mazatec shamanic ceremony in which the participants rolled up salvia leaves and chewed them. The effect was profoundly psychedelic, Blosser reported.

Inspired by Blosser's account, Daniel Siebert, an independent ethnobotanist from Los Angeles, distilled the plant's juices to produce white, needle-shaped crystals which he called salvinorum A. Just a tiny crumb of this on his tongue produced what he describes as the most awesome and frightening experience of his life. "Suddenly I lost all physical awareness. I felt as though I were completely conscious and yet I had no body. I wondered if I had died," he says.

“I lost all physical awareness. I felt as though I were completely conscious and yet I had no body. I wondered if I had died.”In 2002, with recreational use of salvia on the rise in the US and elsewhere, Bryan Roth, director of the National Institute of Mental Health's psychoactive drug screening programme at Case Western Reserve University in Cleveland, Ohio, took an interest. He discovered that salvinorum A is highly selective for the recently discovered kappa opioid receptor in the brain (Proceedings of the National Academy of Sciences, vol 99, p 11934). Like the other two opioid receptors (mu and delta), kappa is involved in pain sensations. But, unlike the other two, chemicals bound to it can cause hallucinations.

It's still unclear why salvia produces hallucinations. "Some of the experiences people have on salvia may be similar to the psychosis that occurs in late-stage Alzheimer's," says Roth. "There is an increase in the number of kappa receptors in the brains of people with late-stage Alzheimer's."

All studies so far have shown salvia to be non-addictive. It also appears to have limited potential for abuse. "Most people taking drugs are not looking for an out-of-body experience, they want something gentle," says Harry Shapiro from UK drugs information charity DrugScope. "Salvia is so strong that people try it once and never take it again."

Playing with fire

Even so, possession of salvia has recently been made an offence in four US states - Louisiana, Missouri, Tennessee and Delaware - and a federal ban appears inevitable. Thomas Prisinzano of the University of Iowa in Iowa City, who is studying salvia to research new methods for treating substance abuse and pain, believes it is only a matter of time. "If LSD is schedule 1, then salvia will almost certainly be classed the same," he says.

Some researchers would welcome a ban on salvia and other new drugs. One of these is pharmacologist and substance misuse researcher Fabrizio Schifano of St George's Medical School in London. He says that the main problem with psychoactive substances - and hallucinogens in particular - is that they may incite psychosis. "How do you know if someone will have a sensitivity to the drug?" he says. "I am really worried by the prevalence of these drugs, and the fact that most users get their information from the internet. It is not peer-reviewed research, just people's opinions, and that is very dangerous."

Tim Kendall, deputy director of the Royal College of Psychiatrists research unit, says: "When you take salvia you are playing with fire. People can be very damaged in terms of their personal functioning. They frequently have flashbacks that intrude into their life, which can be almost like a post-traumatic stress problem after very bad experiences."

"My recommendation is that people should keep their minds clean," adds Roth.

Others believe that knee-jerk bans are the wrong approach. People have a natural drive to enter alternative states of mind, argues Richard Boire from the Center for Cognitive Liberty and Ethics in Davis, California. "The role of governments is to prevent harm to people and society from dangerous drug use. I think the government has lost sight of this and now thinks its role is to stop people from entering other mindsets."

For governments intent on pursuing prohibition at all costs, there is a sobering thought. For every banned psychoactive substance there are dozens more that remain legal. The legendary pharmacologist Alexander Shulgin has synthesised more than 230 novel designer drugs, and according to psychologist John Halpern, associate director of alcohol and drug abuse research at Harvard University, there are dozens of legal hallucinogenic herbs besides salvia that are already widely available on the internet and growing in popularity (Life Sciences, vol 78, p 519). What is more, there is clearly a demand for the stuff, and plenty of people like Bowden willing to supply it. Salvia, BZP and kratom may be on the way out, but others will take their place.
Salvia Divinorum
'Magic mushrooms'
The Good Drug Guide
The Doors of Perception
Benzylpiperazine (BZP)
Kratom (Mitragyna speciosa)
MDMA: Utopian Pharmacology
Religious Teatime and the High Court
Albert Hofmann's LSD : My Problem Child
Chemical Enlightenment, Psychedelic Research