This article was taken from the February issue of Wired UK magazine. Be the first to read Wired’s articles in print before they’re posted online, and get your hands on loads of additional content by subscribing online.
The New York State Psychiatric Institute looks like a bastardised version of the Louvre’s glass pyramid, sliced down the middle and hacked on to the side of a low-rise tower. Three floors up is the lab where Carl Hart conducts experiments that, once explained, invariably prompt the same response: is that legal?
Hart pays volunteers to take ecstasy, methamphetamine or cannabis. He then monitors everything they do, eat, drink and say. He draws blood on the hour, sometimes more frequently. He searches their kitchen waste to see if they didn’t finish any of their food. And to top it off, Hart’s recruits — who live in a windowless, fully surveilled apartment for up to three weeks — spend hours taking computer-based cognitive tests, clicking away in a drug-induced euphoria, or a drug-withdrawal dysphoria.
Though Hart is a popular lecturer with a joint appointment in the psychology and psychiatry departments at Columbia University, it’s his research that has made him an increasingly prominent figure in academic circles. Unlike any other in the US, Hart’s lab comprises a full-scale laboratory-cum-apartment (called the ResLab, short for residential laboratory) and a nearby surveillance cubby, informally known as the control room.
From this nerve centre, research assistants record data, administer tests and keep a watchful eye on Hart’s subjects 24 hours a day. The assistants watch live video feeds on 14 black-and-white monitors, and they listen in on conversations picked up by strategically placed microphones with individual volume controls. The surveillance is all-electronic — no one-way mirrors here — and its panopticon completeness would have made Orwell giddy.
For the most controversial studies, those that involve repeated high doses of insufflated meth (snorted up the nose to simulate the way the powdered form is often taken on the street), Hart has a separate room called the MethLab, where his subjects are hooked up throughout the day to an electrocardiogram, a blood-pressure monitor and a pulse oximetry finger sensor. Electrodes and other read-outs are connected from their bodies to wires that pass through a small hole in the wall, into a machine called the Poet Plus 8100 Vital Signs Monitor.
The study of drugs of abuse has traditionally relied on animal models — mice, dogs and sometimes monkeys. But Hart’s focus is part of an emerging insight: the best way to pinpoint the effect of a drug such as meth on humans is to study it in humans. His results have started to back this up, confirming that much of what we thought we knew about drugs of abuse may well be wrong. For example, his research demonstrates that marijuana can cause withdrawal, methamphetamine and ecstasy are difficult for experienced users to tell apart, and that meth — not ecstasy — increases acute cognitive performance, talkativeness and sociability. In the process of making these discoveries, Hart is rewriting the theory of addiction and pointing the way to better treatments. At the same time, his data raises intriguing questions about the complex and poorly understood connections between the ebb and flow of specific neurotransmitters and behaviour.
It could be a scene from a suburban kitchen: four Tupperware containers neatly lined up and ready to be carried off for lunch. Except here in the ResLab, each holds a disposable lighter and a marijuana cigarette; over the end of each joint is a black Bic pen cap with its clip removed: the cap helps standardise the dosage and also disguises the colour of the drug so the smokers don’t draw conclusions about the strength of what they’re smoking and react accordingly. Seven potential subjects are ready for their first round of dosing. They’re here for a kind of try-out: four will make it into a study that involves getting paid $70 (£43) a day to smoke high-grade dope. All are consummate tokers who smoke daily and have no desire to quit, but if they can’t hold their pot now or they freak out getting high in the lab, they won’t make the cut. The ResLab’s subjects are recruited by word-of-mouth, Craigslist and newspaper ads. They must pass physical and mental tests, sign a lengthy disclaimer and be avowed users of whatever drug they will be dosed with in the lab.
One wall away, in the control room, post-doctoral fellow Ziva Cooper is leaning against a cabinet, a finger on the light switches that will signal the recruits to start smoking, another finger on her stopwatch. When she works the lights, smoking commences; by the second puff, the volunteers are sputtering like two stroke lawnmower engines. “Three years ago, man, I had this cat, Cindy,” one of the subjects blurts out to no one in particular as the coughing subsides. Though his appearance is obscured by the fuzzy video feed, the assistants in the control room hear his booming voice over their speakers. Just on time, they nod to one another — looks like the marijuana is starting to kick in. “We thought Cindy might be lonely, yo. ‘Let’s get her a playmate. Let’s get her a dog, yo,'” he says after a pause. “But my girlfriend was like, ‘No, let’s get her a cat.’ Long story short, the cats don’t get along. The little cat ain’t little no more — she’s so agile. All I hear is bump-bump-bump-skeeeooow.” He pauses for a moment, searching for the right phrase. “The little cat be fucking up the big cat!”
In the control room, the research assistants themselves seem to be succumbing to what Cooper describes as a “psychological contact high”. They’re munching away on a stoner’s hit-parade of snacks: McDonald’s burgers, french fries, Skittles, bags of crisps. The pot-smoking volunteers, meanwhile, have the munchies for real. A research assistant brings in food that the subjects previously ordered via computers in the ResLab. It’s largely microwaveable stuff: chicken nuggets, mini-hamburgers, anything that can be prepared with a few taps of a button and minimum waiting. The subjects rush off to their rooms with their orders, and moments later a humming chorus of microwaves comes drifting over the speakers. Next, a cacophony of plastic being torn, wrappers scrunched, and finally it’s quiet again.
After the try-outs are over, a few days of heavy dosing are followed by a few days of placebo, and the study bears fruit: four ornery study subjects going through marijuana withdrawal, complete with irritability, decreased food intake and trouble sleeping. It may seem banal, but it’s this kind of basic research observation that, until recently, had never been made. The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, revised in 1994, with minor changes in 2000) includes withdrawal syndromes for various substances, including nicotine, but not marijuana. When DSM-V is released in 2012, that may change.
Carl Hart has shoulder-length dreadlocks, gold hoop earrings and a golden incisor. The look suggests a pirate in corporate attire. In conversation, he’s exuberant and inquisitive and seems younger than his 43 years. In a field typified by older white men, his appearance induces a sort of cognitive dissonance in everyone from peers to law enforcement. “I remember the first talk he gave at a major professional meeting,” said Chris-Ellyn Johanson of Wayne State University in Detroit, a veteran drugs-of-abuse researcher. “He stuck out. It was kind of unforgettable. But you know, he gave a great talk. It’s a terrible thing to admit, but we just don’t have very many blacks in the field, let alone someone who is comfortable enough with himself to wear dreadlocks and make it professionally.”
Unfortunately, not everyone has been as open-minded. Hart recalls how a few years ago, while completing a prestigious Intramural Training Award fellowship at the National Institutes of Health outside Washington DC, a police officer picked him up outside a laboratory and put him into an impromptu one-man identity parade as a suspected mugger (though his government-issue ID was still hanging around his neck). And on the first day of a postdoctoral fellowship in San Francisco, he was harassed by cops for “loitering” outside the laboratory where he was waiting to meet his adviser. There was a time when the police had good reason to be suspicious of Hart, who grew up shuttling between Miami’s public housing projects and the lowest rungs of the city’s black middle-class. He flirted with violence and petty crime before joining the military to escape the drug-dealing, homicides and prison sentences faced by many of his peers.
A couple of winters ago, Hart travelled to New Orleans for a conference organised by the Drug Policy Alliance, a body dedicated to finding alternatives to the “war on drugs” (Hart sits on its board, along with such notables as the investor-cum-philanthropist George Soros and Jason Flom, chairman and CEO of Capitol Music Group).He gave a brief speech and then continued on to the city where he grew up.
On one of those nights in Miami, Hart was driving down Interstate-95 when he decided to pay a visit to his old haunts. Passing by the dilapidated strip malls — the Yamaha dealership and Burger King and the 23-hour drive-through liquor store — Hart’s mind was flooded with memories. He recalled messing around with a .22 rifle that a friend stored in his car: they never fired it but they did spend time pointing it at random passers-by, playing at being adolescent hoods.
Another time, Hart and his high-school basketball teammates, upset about losing a game, left a fast-food joint without paying for their food. As Hart stood up, the waitress grabbed him — Hart knocked her over and walked out. Though he never got in trouble for this, or for much else, Hart was conflicted: these malicious acts gave him a rush of power and pleasure but also a certain sense of guilt. Nowadays, he can’t tell these stories of his youth without wincing. “I wasn’t too stupid to know that I had to get the fuck out — quickly,” he says about leaving Miami.
After high school, Hart signed up for the US Air Force. He took university classes on the bases where he was stationed, primarily, he says, because his military buddies were troublemakers and he wanted a back-up plan if he got kicked out of the service. When Hart satisfied his commitment to the Air Force in 1988, he moved to North Carolina, following a girlfriend he had only just started seeing. Luckily for him, her stepfather was a professor at the University of North Carolina, Wilmington, who arranged for Hart to enrol there (though Hart and his girlfriend eventually split up). Hart had enjoyed studying psychology in the Air Force; now he became obsessed: it opened a window into the hidden world of human motivation. By the time he graduated with a double major in sociology and psychology, he had become a serious student and his work ethic had caught the attention of some of his professors.
One of them, Robert Hakan, invited Hart to work as a research assistant in his electrophysiology lab, studying morphine and nicotine in mouse brains. Hakan also introduced Hart to the man who had been his PhD adviser, Charles Ksir of the University of Wyoming. On Hart’s first visit to Wyoming, Ksir took him to a basketball game. “You see those black guys out there?” Ksir asked. “That’s the most black people you’re going to see in Wyoming in one place.” It wasn’t an orthodox pitch to a prospective PhD, but the candid remark set the stage for hours of conversation, covering everything from race to neurobiology to politics. With Ksir as his adviser and mentor, Hart went on to earn his PhD from the University of Wyoming, studying the neurobiology of nicotine in animals.
Hart then took a series of post-doctoral places (at University of California, San Francisco, Yale and Columbia) working with human subjects. He met Marian Fischman, a renowned drugs-of-abuse researcher, who invited him to apply to Columbia’s medical centre. Her pioneering work giving cocaine to humans made possible the studies Hart now conducts.
In the 60s, opiate dependence had been explained in terms of sexuality. The theory was that since opiates reduce sex drive, heavy use must be an attempt by homosexuals to resolve the neurotic conflict between the id’s sexual desires and the superego’s insistence on heterosexuality. Animal experiments, however, threw doubt on this theory. In the 70s, neuroscience and chemical explanations for mental disorders replaced the psychoanalytic approach. Everything from criminality to mental illness to drug addiction, it was believed, could be induced or eliminated by tinkering with the brain’s chemical balance. The brain was no longer a sealed black box. It was machine-like and knowable.
By the 80s, drug-induced chemical changes could be investigated not only in the brain as a whole, but systematically in specific brain regions in animals. A particular system of interest was the mesolimbic dopamine pathway in the nucleus accumbens, the brain’s “reward centre” — a system responsible for causing animals (and, if we are to trust the animal model, humans) to feel good when they eat, have sex or get intoxicated on certain substances. Dopamine, it was theorised, was a reward used by healthy brains to encourage evolutionarily beneficial activities like breeding. Certain mental illnesses, however — or drug use — short-circuited the system.
The animal model enabled a neurobiological explanation for drug addiction that went something like this: drugs of abuse cause increased dopamine activity in the brain, which causes stimulation and euphoria; during repeated drug use an addicted brain rejigs its dopamine activity, perhaps even its structure, causing the brain’s owner compulsively to seek out the drug to feel its pleasurable effects. The theory accurately predicted that dosing cocaine-addicted animals with a dopamine antagonist — a substance that dampens dopamine receptor activity — would also dampen self-administration of cocaine.
By the time Hart was a post-doc, a small group of researchers was trying to extend this treatment to cocaine-addicted humans. Several dopamine antagonists that had worked in animals failed completely when tried on humans. The reason, Hart suspected, was that the dopamine theory of drug addiction was a gross oversimplification when it came to humans, and he began pursuing this line of thought. In 2004, he gave cocaine users gabapentin — a drug that blocks dopamine activity by pumping up levels of an inhibitory neurotransmitter called GABA. Sure enough, when dosed with cocaine, the subjects in the study felt less than their normal euphoria and stimulation — but they continued to self-administer the drug any way. Next, in the first study of its kind in a residential lab, Hart administered 400 milligrams a day of modafinil — the “stay awake” drug marketed as Provigil — to a separate group of cocaine addicts. In response, the study subjects decreased their self-administration of cocaine.
What is significant about these studies is that suppressing dopamine activity in the so-called reward centre of the brain may reduce the subjective effects of cocaine — the stimulation and the euphoria — without halting the drug’s use (at least in humans). If the reward theory of addiction is correct, how is this possible? And how can a drug like modafinil, peculiar in being a stimulant that is not linked primarily to dopamine and euphoria, cause human addicts to ramp down their cocaine use voluntarily?
The crowd at Brooklyn’s Union Hall whoops and applauds as Hart steps onstage and says, flashing a smile, “You make a scientist feel like a rock star.” He’s here to deliver a lecture at the monthly gathering organised by a group called the Secret Science Club. With his dreadlocks and sunglasses, Hart looks like a professorial Stevie Wonder. His talk tonight is entitled “Methamphetamine: A Good Drug Gone Bad”.
After covering a bit of history — including a 50s advertisement in the Journal of the American Medical Association promoting amphetamine use among bored housewives — Hart summarises the conventional wisdom about meth: according to animal studies, it beats even cocaine in its ability to boost dopamine activity in the brain’s reward centre. Meth’s reward stimulus is so strong, the thinking goes, that its users will compulsively seek out the drug no matter the financial cost, damage to health or stated desire to quit. All this is backed by leading researchers and the US government itself. The National Institute on Drug Abuse (NIDA) describes meth addiction as “a chronic, relapsing disease, characterised by compulsive drug-seeking and use, which is accompanied by functional and molecular changes in the brain”.
But Hart is sceptical of a model that defines addiction as a neurochemically ordained mental disorder of impulsivity and faulty decision-making. Such a model assumes that drug use is always driven by the irrational desire for pleasure, even in the face of grave life consequences. The possibility that drug use may be fuelled by rational choices is never even considered. Could such a theory be as faulty as an earlier era’s belief that opiate addiction is mainly a result of conflicted feelings about one’s sexuality?
In quick succession, Hart shows the Union Hall audience a series of slides containing data from ResLab and MethLab studies. The sequence demonstrates that humans subjected to simulated shift-work show significant cognitive impairment when rotated between normal working hours and overnight schedules. In the next sequence, he discusses a study in which these participants were given small doses of methamphetamine, and their shift related cognitive impairment was significantly reduced — they made fewer mistakes and completed cognitive tasks more quickly than when they were given placebo doses. Of course, says Hart, the military has known about this for years, which is why some pilots are offered dextroamphetamine for long-haul bombing missions.
Hart next tried offering these participants the choice between a low dose of meth and a small monetary voucher, at different times of day. The prediction was that, meth being a potent reinforcer, users would take it compulsively; what he found was that people would take it in the morning but not in the evening, when it would stop them sleeping — using it to get through the day in the same way office workers self-administer caffeine; and if the monetary reward was large enough, they would pass up the dose. These findings call into question the notion that addiction is driven by the reward of a chemically induced euphoria and that meth — legally prescribed to treat ADHD, narcolepsy and obesity — is the destructive drug so maligned by the NIDA and the popular press. Hart’s conclusion was that his subjects were indeed making rational choices about their drug use.
“The dirty little secret,” says Hart in his office one afternoon, is that most of the funding for his work comes from places like the NIDA, which pays for 85 per cent of the world’s research on drugs of abuse. Its mission, according to its website, is “to lead the Nation in bringing the power of science to bear on drug abuse and addiction”. “When I teach my classes,” he says, “I tell the students, ‘Look, I’m in this, too. I get money from the hysteria.'”
He says he agrees with the NIDA’s mission, but that the focus on the pathology of drugs is disproportionate. According to the US National Survey on Drug Use and Health in 2007, 19.9 million Americans had used illicit drugs in the past year, of whom a total of 6.9 million were classified as having a dependence (3.7 million dependent on illicit drugs alone, 3.2 million dependent on drugs in combination: that compares with 15.5 million classified as dependent on alcohol). So nearly two-thirds of drug users don’t fit any framework of pathology. How can we understand the psychological, biological and social implications of drug use if we aren’t studying how illegal drugs are actually used?
There is not much money for studies outside the narrow theories of reward, addiction and impulsivity championed by the NIDA. However, in late 2008, Nature ran a piece entitled “Towards responsible use of cognitive-enhancing drugs by the healthy”. Its authors wrote: “Today, on university campuses around the world, students are striking deals to buy and sell prescription drugs such as Adderall”– a mixture of amphetamine and dextroamphetamine — “not to get high, but to get higher grades.” Human use of chemical enhancement is inevitable, they argue. More recently, a Wired writer (issue 06.09) wrote about her experiences taking modafinil, and the New Yorker ran an article about “neuro-enhancement”, concluding that wide spread use of stimulants and other drugs to enhance cognition is already taking place, and that we’d be wise to understand its implications. Hart’s bold work has led to his being granted tenure at Columbia — in contrast, last year in the UK, Professor David Nutt was sacked as chair of the Advisory Council on the Misuse of Drugs, after he argued that ecstasy and LSD are less harmful than alcohol and tobacco. Unlike government policy, scientific and public opinion have moved from the old days of just saying no.
To many, even asking questions around this topic is dangerous. If illicit drug use, or at least some non-trivial volume of it, is based on rational decision-making by people who can’t be classified as drug abusers, then the science of illicit drug use will need to be rewritten, drug policy will need to be reconsidered, and organisations like the US’s NIDA will need to be re-imagined or become an anachronism. In this light, who can argue with Hart’s dogged call to put more data behind smarter drug policy?
Carl Hart’s drug-chemistry basics
“Meth enhances neurotransmitters that play a role in alertness and in increasing euphoria – it keeps you up, helps you be more alert and even to focus. The downside: when you need to sleep, you can’t. And excessive sleep loss can play a role in depression, psychosis and all the rest.”
“All the same things that apply to meth apply here – except that the effects of cocaine are a lot more short-lived. As with meth, you have sleep deprivation, decreased food intake and increased cardiovascular activity, which can increase likelihood of a heart attack or stroke.”
“People want to hang out with each other, but they talk a lot less on cannabis than on meth, cocaine, alcohol – all the other drugs. The main downside is lung toxicity if you’re smoking. Novice users are more likely to experience paranoia at large doses. The average potency has risen a little bit, but this isn’t new; humans have always known how to increase the potency of cannabis.”
This article was taken from the February issue of Wired UK magazine. Be the first to read Wired’s articles in print before they’re posted online, and get your hands on loads of additional content by subscribing online.