If you could take the high out of drugs, what would be the point in taking them? Sujata Gupta meets the unorthodox doctor who thinks he can block some of the world's most addictive pills.
Toru had always been anxious as a child, but the problem worsened when he was 19 and attending college in Tokyo, Japan. A social science major, he would feel his heart race every time he had to present in front of his class. A psychiatrist prescribed clonazepam, an anti-anxiety medication that belongs to a class of drugs known as benzodiazepines (which also includes Valium and Xanax).
Initially, Toru felt calmer, even when he had to speak in public. Soon, though, the drugs' potency began to wane and, after about a year, Toru quit taking them. His anxiety escalated. He stopped sleeping and began experiencing panic attacks, one so severe that he called an ambulance to take him to the emergency room. So Toru did the logical thing: he went back on the drugs.
Despite his struggles, Toru completed his degree and began working in information technology. But he had developed a temper and struggled to hold down a job. At a particularly low point, he destroyed a computer and got fired. After that incident, Toru stopped looking for work. Periodically, he would try to go off the meds again, but the withdrawal symptoms always proved too severe.
Toru's mother, Machiko, was the first to realise just how bad things had become for her son. He was never angry as a child, she tells me emphatically — the drugs changed him.
As Toru floundered, Machiko began calling his doctors for help, but they stonewalled her. "I was seen as an interfering mother," she says. Finally, seeking an escape from another winter in Japan, she decided they should go on a sort of extended drug treatment holiday, winding up in Brisbane, Australia. There they met with a doctor who told Machiko: "If Toru were my son, I would go directly to Dr George O'Neil."
George O'Neil is an unlikely saviour for the world's benzodiazepine addicts. A large man with a cherubic face and slight paunch, his expertise lies not in addiction but in obstetrics and infertility.
I first meet O'Neil at his summer home in Lancelin, about an hour's drive from Perth. The yard is full of scrubby bushes and meandering trails and, a mile off, one can see the faint outline of the ocean. The single-story house is long and disjointed — the only way to traverse from one room to the next is to exit and re-enter from outside — lending the place the feel of a motel. This is fitting. Here, the O'Neil brood (six children, five spouses and nine grandchildren with O'Neil and his wife, Chris, at the helm) congregate away from Fresh Start, the drug rehabilitation clinic O'Neil has run for two decades with near-maniacal fervour.
Chris tells me that the location is intentional. She's had addicts drop by their house in Perth and harass her autistic son, Rodney. Once, a deranged patient came to the house and held Chris and her youngest daughter, Jocelyn, then 17, at knifepoint. The patient backed down when Jocelyn cool-headedly pointed out that her anger lay with her father and not them. It was then that Chris realised they needed a safe haven.
O'Neil's quixotic quest to cure drug addiction began in the mid-1990s when a young woman approached him seeking help for her husband, who was hooked on heroin. Now she was 15 weeks pregnant and terrified about having to raise the child alone. "You're a Christian and a well-known scientist," she pleaded. "Surely there's something you can do." The woman was persistent and "very lovely," O'Neil says. She came back every month for 18 months begging for help.
O'Neil may have seemed an odd person for the woman to seek out, but she knew about his other life as an inventor. In his 20s, when O'Neil was completing his obstetrics training in South Africa, he created a localised water filtration system to prevent bacterial diseases caused by inadequate access to clean water, an analgesic inhaler so child burn victims could avoid needles for pain relief and a portable device to rehydrate sick children without resorting to an IV. In the early 1980s, O'Neil invented a catheter that halved the rate of urinary tract infections experienced by paraplegics. To build the device — which remains one of the most widely used catheters in the world today — he established GO Medical (the 'GO' comes from his initials), a nonprofit medical device company, in 1984. The catheter was a money-maker and ultimately freed up O'Neil to devote his life to rehabilitating drug addicts.
"In one short lifetime you could concentrate on 2000 inventions," O'Neil tells me, but there's always one that really matters: "There's always a pearl." He found his first pearl in China. There, O'Neil attended a talk by a young scientist working with naltrexone, a drug that appeared to take the high out of heroin (a considerably more potent form ofthe drug, known as naloxone, was already being used to reverse the effects of an opiate overdose).
O'Neil had his eureka moment. He realised that tweaking blockers like naltrexone for addicts could rein in their cravings. He returned home to Australia and told the woman that he had figured out how to help her husband.
O'Neil's approach is beguilingly straightforward. Drugs known as 'blockers' have been on the market for decades. At high doses, they reverse lethal overdoses, but patients undergo a rapid and excruciating detox. O'Neil suspected that at extremely low doses, blockers could take the high out of opiates like heroin without such a painful detox.
Getting high requires fooling our bodies' cells. Normally, these cells keep things running smoothly through a system of keys and locks. 'Keys' — hormones or neurotransmitters — gain access to cells by binding to specific receptors — 'locks'. Drugs known as 'agonists', including opiates (such as prescription painkillers and heroin) and benzodiazepines, mimic the body's natural hormones or neurotransmitters and essentially pick the lock. By contrast, antagonists, or blockers, make it impossible for agonists to gain entry by jamming the lock. In so doing, blockers take the high out of drugs. Why, reasoned O'Neil, would an addict continue taking a drug if it no longer feels good?
When O'Neil first started working with naltrexone, he offered it to patients as a daily pill. The formulation was too strong and triggered a rapid, painful detox. "It half killed me," one of O'Neil's patients, who tried the treatment in 2001, told me. Moreover, because forgetting or neglecting to take the pill was easy, staying on naltrexone required pure willpower. As Gary Hulse, a psychiatric researcher at the University of Western Australia and one of O'Neil's longtime collaborators, puts it: "Why would any self-respecting heroin user take it?"
O'Neil set to work creating a method of delivery that the addict couldn't control. He developed a polymer to encapsulate the pill and make it release more slowly into the bloodstream, along with a medical device — which works almost like a Pez dispenser — to implant the pills into a patient. O'Neil's naltrexone implants can last for almost a year and can be re-implanted indefinitely. Noel Dowsett, the nurse in charge of Toru's care and a former heroin addict, is on his 11th implant. "Methadone you always felt medicated, albeit subtly," says Dowsett, referring to the opiate given to injection users that is supposed to control cravings without inducing its own high. When he's on naltrexone, though, Dowsett says all that goes through his mind is: "God, I'm free."
In the mid-2000s, O'Neil attended an addiction conference in London where he heard a talk by an Italian researcher. Gilberto Gerra was presenting his research on flumazenil, a drug that appeared to block benzodiazepines in much the same way naltrexone blocks opiates. O'Neil was intrigued. He'd found his second pearl.
Benzodiazepines are among the most widely prescribed class of anti-anxiety drugs in the world — and for good reason. Several years ago, Sean Hood, a psychiatric researcher at the University of Western Australia in Perth, conducted a study of social anxiety sufferers in Bristol, UK. "We looked at people who had been unwell for social phobia. On average in that group, they'd been unwell for 28 years before they got treatment. And you give them one of these benzodiazepines, within 40 minutes, they say, 'My anxiety is better'."
Benzodiazepines were first introduced in the early 1960s, and just a decade later they had become the most widely prescribed class of drugs in the world. In the USA between 1969 and 1982, more prescriptions were written for Valium than for any other drug. Soon, however, signs began to emerge that the drugs were far from benign. They have been linked to grogginess, cognitive impairment and dementia. Worse, addiction can set in within weeks, even at low doses, and the drugs can actually trigger the very same conditions they're meant to control, such as panic attacks and seizures. Some users who have tried to quit, like Toru, find that withdrawal symptoms linger for months or even years. (One man told me that coming off both meth and heroin was easier than coming off benzodiazepines.) Many countries have now adopted drug policies stipulating that benzodiazepines be used for no more than 2 — 4 weeks, but such recommendations are frequently ignored.
Flumazenil was first identified as a benzodiazepine blocker in 1981 while scientists were trying to create an even faster-acting benzodiazepine. The drug had a half-life of just 7 to 15 minutes, making it useful for quickly reversing an overdose. The FDA approved flumazenil for that very purpose in 1991.
I call up Gerra, who's now based in Austria and helping low-income countries establish drug policies with the UN. From 1983 to 2003, he was a practicing physician and spent a lot of time in the ER treating patients who had overdosed. Reversing the overdose with naloxone worked, but patients typically woke up angry and hostile. "The patient was dying in a pleasurable way," Gerra explains, and then "we put him through profound chemical withdrawal."
Complicating matters, many of those patients had taken both opiates and benzodiazepines, a particularly lethal combination — according to the US Centres for Disease Control and Prevention, about 30 per cent of lethal overdoses involve the mix, which killed actor Philip Seymour Hoffman in 2014. In those cases, Gerra suggested that the hospital also administer flumazenil in as low a dose as possible to avoid hostility during withdrawal. The patients responded beautifully. There was, recalls Gerra, "no terrible reaction at all." Flumazenil had the potential, Gerra realised, to become "the naltrexone of benzodiazepines".
Gerra's talk in London inspired O'Neil, who set to work developing a blocker for benzodiazepine addicts. O'Neil knew he wanted something long-acting and addict-proof, like the naltrexone implant. He initially developed and patented a pump, a straightforward device akin to an old insulin pump, which allowed flumazenil to be delivered intravenously over several days on an outpatient basis. But getting addicts to comply with the pump was difficult as it could be removed at will, so O'Neil created slow-release flumazenil tablets designed to go inside an implant.
Jon Currie, director of the addiction medicine unit at Saint Vincent's Hospital in Melbourne, Australia, raves about both the pump and the implant. "I haven't done a gradual reduction of benzodiazepines in ten years now," he says. "I just use flumazenil. It's absolutely revolutionised the benzodiazepine withdrawal process."
In early 2014, Toru and Machiko flew to Perth to meet with O'Neil, who immediately started Toru on the flumazenil pump before switching him over to the longer-lasting implant. In November, when I meet Toru at the small apartment in Perth he shares with his mother, he has just had his third implant.
Broad-boned with a mop of thick, slightly greasy black hair, Toru recounts his story in halting English. Returning home to face all the stressors that prompted him to take anti-anxiety meds in the first place scares him most of all, he says. "If I go back to Japan now, I don't think I can stay away from benzos." Yet everything about his life in Perth feels temporary. The furnishings in the apartment are sparse and the walls unadorned, save for several 8 x 11 sheets of paper tacked up with tape and all bearing the same inspirational message in colourful script: "Walk the path! Say Little, Love Much, Give All, Judge Not, Shine up, Keep On, & See Good," followed by footprints walking off the page.
"His level of anxiety is really horrific, the most severe I've ever seen," Toru's nurse, Noel Dowsett, says when O'Neil and I reach him over the phone for an update on Toru's condition. After 25 weeks without any benzodiazepines, Dowsett adds, Toru has managed to get his hands on some pills. O'Neil is unfazed. After we hang up, he tells me Machiko and Toru have been at loggerheads. O'Neil thinks it's good that Machiko has to return to Japan briefly to renew her tourist visa. He hopes that Toru might stabilise during his mother's time away.
Getting off drugs is only the first step to recovery, a basic truth that O'Neil learned the hard way. I ask what happened to that woman's husband — the one who got him into treating drug addiction so many years ago. O'Neil tells me he stayed sober for 18 months before returning to heroin. His wife said she was done forgiving and walked out. "Two days after she left, he killed himself."
Over time, O'Neil developed his own iteration of the 12-step programme (the popular rehab programme in which addicts must admit powerlessness over their condition and accept the presence of a divine power). He called it PHREEEEE, for pharmacology (the implant); home; relationships; environment; education; employment; entry to our community; and exit where you live. To help addicts reach 'PHREEEEE-dom', O'Neil has launched an empire. Besides the clinic, he has temporary detox houses (where addicts can go to sober up before receiving implants), long-term facilities located far away from Perth (so recovering addicts can rehabilitate away from their friends and dealers) and therapists, not to mention a rotating stream of guests who visit the clinic to observe the work he's doing. On the day I visit, these guests include a paralegal and an artist.
Toru tried staying at Northam, one of O'Neil's long-term rehab clinics, but with his limited English he struggled to communicate with the other lodgers. Isolated and overwhelmed, he soon returned to Perth.
Now, once per week Toru attends a therapy session with Zdravko (Tony) Cerjan, a Yugoslavian native with a thick accent and black frames reminiscent of those worn by Woody Allen. When I arrive, Cerjan is seated on an orange couch; the other four couches in the office are all grey. Toru and Cerjan discuss the new sleeping med that Toru has been prescribed. "I took it for the first time yesterday," says Toru, whose rumpled clothes and dishevelled hair make it appear that he just rolled out of bed. "You convinced yourself you couldn't sleep. You created the problem," Cerjan lectures, sounding more like a self-help guru than a medical specialist. Cerjan then suggests that Toru keep the pill and some water by his bedside and wait to take the pill until he's sure he can't sleep. "Repeat the routine all week," he prescribes. Toru, face expressionless, agrees to comply.
The Fresh Start Clinic is situated in a relatively affluent district of Perth. I meet O'Neil at 10.30 on a Wednesday morning. The waiting room is full and many patients loiter on the bench outside or squat under a nearby tree. The more solitary sorts puff on cigarettes some distance away from the group. To appease the area's otherwise well-heeled clientele, the clinic recently hired an artist to liven up the building's exterior with enormous painted butterflies.
O'Neil takes me on his rounds. I listen as an indigenous couple recount how they met during a stint at rehab. The woman sobs when she tells O'Neil that she has lost custody of her children. I meet a young meth addict whose right arm is covered with an intricate dragon tattoo. He refuses any pain medications so that he can drive home immediately after receiving his naltrexone implant. I hold the hand of Vikki, a woman with purple hair and an easy laugh. She shakes constantly, a side effect of the Seroquel, a powerful antipsychotic that she takes to stay calm. O'Neil inserts another round of naltrexone into her abdomen, just below the belly button — insurance against returning to heroin, Vikki says.
Lastly, there's Amy. Skinny, with a thick mane of brown hair pulled back with a ponytail holder and inch-high platform flip-flops, the only obvious sign of her addiction to heroin and benzodiazepines is her teeth, which are largely absent. By her own accounting, her life has recently turned around. With the help of a naltrexone implant, she's quit the heroin, and now with the flumazenil she's down to just a handful of benzodiazepines per day (unlike Toru, who never went above a few pills per day, Amy had been downing them by the bottleful). Today, she's switching from the short-acting pump to the implant. Her boyfriend, Aeden, strokes her head as O'Neil slices through the skin near her naval.
Over the years, O'Neil has experimented with naltrexone on opiate, meth, alcohol and gambling addicts. He suspects the drug can help overeaters control their cravings. Meanwhile, he's testing flumazenil on a patient with Parkinson's disease (it appears to reduce tremors) and hypersomnia, a disorder that causes people to sleep all the time. He has reason to believe that flumazenil might also help treat ADHD. At one point, O'Neil puts me on the phone with a 71-year-old woman named Pat, a heavy smoker who has been using a flumazenil nasal spray O'Neil invented whenever she has the urge to light up. "The next planned study that I'm going to do in this area is I want 40 smokers to come in Saturday morning and get the nasal spray," O'Neil says. "On Monday morning I'm going to tell 20 of them which are the duds and which were the real ones. And then I'm going to find out who stopped smoking over the weekend."
Yet O'Neil's loose approach has made it hard for him to market the implant. "Naltrexone implants have not been approved for human use in Australia due to a lack of results from clinical trials demonstrating their pharmaceutical quality, safety and efficacy," reads a blurb on the National Health and Medical Research Council website. Trials of flumazenil are even further behind. As such, O'Neil is limited to using his naltrexone and flumazenil implants for research purposes only. And because the products are not registered with Australia's Therapeutic Goods Association, it's illegal for him to advertise or actively recruit new patients.
Some say that caution is warranted. Alex Wodak, president of the Australian Drug Reform Foundation, argues that blockers like naltrexone trigger too severe a withdrawal and even lead occasionally to death. They have not, he says, been subject to rigorous scientific review (Wodak is also critical of the US Food and Drug Administration's 2006 approval of Vivitrol, a naltrexone injection that works for 30 days).
"It's one thing [for O'Neil] to be able to talk to religious groups about the wonderful work he's doing and get donations to continue it," he says. "If he wants to be taken seriously, there's only one way to do that and that is to publish in high-standing refereed journals."
In an email, O'Neil counters that Wodak is ignoring "more than 30 publications relating to our naltrexone implants in high ranking journals including two randomised trials here in Australia and Norway. While there are only 3 trials published on flumazenil work by our group this work is the most advanced in developing practical treatment for benzodiazapines."
Following protocol, O'Neil says, means prolonging patients' suffering. "Normally people plan a clinical trial and they don't start until the money comes in," he told me in Perth, "I have an idea on Monday and I get something made on Tuesday and I've got a patient on Wednesday and I say, 'This medicine might help you.'"
Blockers square with O'Neil's world-view. He is deeply critical of the USA's push to legalise marijuana. And he questions programmes that rely on methadone. Why would you treat opiate addicts with opiates? O'Neil asks. A "20-year-old will become a 40-year-old who's taking methadone every day." Wodak and others, by contrast, argue that methadone works. "Some people object to an agonist drug being given to people with an addiction to that agonist drug. People can have whatever views they want," Wodak says. "It is clear that methadone is an effective, safe and cost-effective drug."
The divide between the pro- and anti-blocker camps can start to feel almost religious. Staying on drugs, even maintenance drugs, says Peter Coleman — head of the rehab clinic The Coleman Institute and the only practitioner I can find in the USA using flumazenil to treat benzodiazepine addiction — means that the user never quite enters reality. "The Buddha said life is painful," Coleman says. "The goal is to transcend that and stop seeing it as painful and just see it as the journey."
Yet it's not entirely clear which camp flumazenil falls into. When Gilberto Gerra's patients experienced no hostility during withdrawal, he began to suspect that flumazenil calmed people by allowing some very limited benzodiazepine activity. His subsequent investigation found instances where neuropsychologists working with flumazenil had reached the same conclusion. When he began publishing on his findings in the early 1990s, a representative from the drug's manufacturer, Roche Pharmaceutical, called.
The drug was billed as a pure blocker to reverse a benzodiazepine overdose. When Gerra told the rep that he believed the drug was a very weak benzodiazepine, the company was surprisingly forthcoming. He was told that they were looking into developing a flumazenil pill (at the time, the drug was only commercially available as an intravenous fluid) to treat epilepsy. This was striking as the primary anti-epileptic medication at the time was the benzodiazepine Valium. "I said, 'Friends, if you are saying that you are experimenting with [flumazenil] as a weak anti-epileptic, you are admitting that this is being used like Valium, not a Valium antagonist,'" Gerra recalls.
More recently, Hulse at the University of Western Australia treated a woman for benzodiazepine addiction using flumazenil. Since she still experienced intense anxiety in certain situations, Hulse has been having her take a sublingual flumazenil tablet (another of O'Neil's inventions) every time she feels a panic attack coming on. "When you look at flumazenil," says Hulse, "it's meant to be an antagonist, so it's meant to be neutral — no activity there at all. My observation is that it looks as though it may have agonist action."
"Then the question becomes, will it eventually be found to do the same things as the benzos?" says Hulse. "Could it itself be addictive? Maybe.
In 2014, Hulse and several colleagues published a small study of 24 opiate addicts from Mauritius. Those patients all received naltrexone implants meant to last for six months and then flew home. Researchers outside the clinic observed that, for half a year, every single patient stayed away from opiates. Getting 100 per cent of opiate addicts better after a single 20-minute treatment, O'Neil says, is unbelievable.
O'Neil is not an author on the study — by design. Because Mauritius lies almost 8000 km from his clinic and patients couldn't keep showing up at his door, O'Neil was prevented from, as he puts it, "contaminating the data". Because when it comes to addicts living in and around Perth, O'Neil often puts in an implant and adds another as soon as the patient feels the urge to use again. Sometimes he throws in some flumazenil. His kindness is also his flaw — dosages and timings quickly get murky, making rigorous testing of his methods difficult.
"You can see that he has these areas of brilliance that can really make a difference to people's lives," says Hulse, "but he has very little concept of how to push it through or document it."
As it stands, the entire enterprise O'Neil has built exists perpetually on the brink of financial ruin. Chris, who is better at keeping track of the books than her husband, tells me that Fresh Start and GO Medical have a joint operating budget between AUD$6 — 8 million. Most patients are treated for free, but a minority pay full price for the treatments or contribute $US20 a month. That comes out to maybe a million, Chris says. Private investors tack on another million or so, while the Australian government contributes another $US3 million. The rest of the money trickles in from here and there, including the sale of properties bought long ago with earnings from O'Neil's inventions. When the O'Neils were short on cash last year, for instance, they sold an acre from a 3-acre parcel of land valued at $US10 million. They used the remaining money to buy the property in Lancelin.
The clearest way for O'Neil to make money would be to sell the patent on his implant, and he's had lucrative offers. But the thought of selling makes him queasy. If drug addicts had to buy his treatment, he says, only 3 per cent of his patients would be able to afford the procedure. What he doesn't want is a "middleman" who is going to exploit addicts and make lots of money for himself.
Alternatively, O'Neil could push forward on the research front to legitimise his work. When I ask him why he doesn't run his own studies, he says that his collaboration with Hulse and others at the University of Western Australia lets him dabble in his myriad ideas, while they identify the most promising work and sort out the specifics. "I point them in the right direction for the next trials," O'Neil says.
But ironically, in outsourcing his larger research goals, O'Neil's work could actually bolster benzodiazepine use. Hulse's greatest hope is that once he and other researchers determine proper dosage and delivery methods for flumazenil, doctors will feel comfortable prescribing benzodiazepines beyond a few weeks. Someone like Toru, for instance, could cycle on and off benzodiazepines without coming unhinged. And that, says Hulse, could revolutionise the use of benzodiazepines to treat anxiety.
Toru and Machiko fought about his benzodiazepine use for years. While she believed that even a single pill a day distorted her son's thinking and personality, Toru wasn't so sure. Curing his benzodiazepine addiction wouldn't simultaneously rid him of the debilitating anxiety that has plagued him for more than a decade. While Toru now says he has come around to his mother's side, his recent search for more pills suggests otherwise. "What I see from Toru is almost delinquent behaviour," O'Neil says.
When I leave Perth, Toru's life seems suspended. Absent the discovery of anti-anxiety medications that work as well or as fast as benzodiazepines, his path to recovery remains murky. He fears returning to Japan, where his stressors reached a head, yet he has struggled to learn English, leaving him caught between two cultures. And given his extreme social anxiety, he has met few people outside the rehab clinic. To help keep loneliness — and the drugs — at bay, Dowsett has arranged to stay with Toru regularly during his mother's absence. Just talking to me, Toru admits as I'm about to head out, has been daunting.
As we speak, Machiko tries to reassure him. "Tapering off the medication is the first step," she says. "It takes some time, like language learning. You cannot learn this new language in a second. And there is no silver bullet. You should be very, very patient."
This article first appeared on Mosaic and is republished here under Creative Commons licence.