MitchG's Journal

Manhattan alcoholism clinic, a ruined Wall

Street speculator named Bill Wilson had a

vision. His room suddenly blazed “with an

indescribably white light” and he experienced

euphoria and a godlike “presence”, followed by

on the road to Damascus, Wilson soon

turned away from his old, inebriated life and

became an evangelist — preaching a radical,

spiritual cure for alcoholism.

That cure grew into the modern addiction

rehabilitation industry, which even today is

dominated by Wilson’s Alcoholics Anonymous

(AA) paradigm and its ‘twelve-step’ approach to

recovery. Perhaps unsurprisingly, given its spiritual

origins, this approach has had an uneasy

relationship with the evidence-based culture of

medical research. Both perceive addiction as

a chronic disease; but whereas scientists seek

rationally targeted interventions to blunt drug

cravings, AA and related programmes tend to

feature group therapy, tearful confessions and

the call to “surrender to a higher power”.

In the past few years, however, these two

cultures have been finding common ground.

Neuroscientists have begun to recognize that

some of the most important brain systems

impaired in addiction are those in the prefrontal

cortex that regulate social cognition,

self-monitoring, moral behaviour and other

processes that the AA-type approach seems

to target. “A lot of the treatment programmes

out there are targeting these systems without

necessarily knowing that they are doing it,” says

Nora Volkow, director of the National Institute

on Drug Abuse in Bethesda, Maryland.

Researchers are now searching for ways to

boost these prefrontal systems even further —

not to remove the need for twelve-step and other

behaviourally oriented treatment programmes,

but to enable people with addictions to get more

out of them. “It completely changes the way that

we look at medications,” Volkow says.

Until recently, addiction researchers focused

almost entirely on ‘limbic’ circuits in the brain

that mediate fear and desire. These dopaminefuelled

networks are effectively hijacked by

addictive drugs and behaviours so that the person

ends up wanting, and compulsively seeking,

little else but the next fix. Drugs such as methadone

and naltrexone can blunt the activity of

these circuits, but they are not a cure.

While doing neuroimaging studies at the

Brookhaven National Laboratory in Upton,

New York, in the 1990s, Volkow was one of the

first researchers to suggest that abnormalities

in the prefrontal cortices of drug users might

weaken the systems that normally counteract

regions and their links to the limbic system

have garnered more and more attention, and

researchers are now attempting “a very extensive

evaluation of how the different areas in the

prefrontal cortex participate in the process of

drug addiction”, Volkow says.

The prefrontal cortex — the most recently

one that most clearly differentiates humans

from other species — is the headquarters for

the circuits that help shape feelings and behaviour

according to long-term goals, moral

strictures and social cues. These systems are

extensively wired into limbic

regions, and are often portrayed

as a ‘braking’ system

to resist impulsive behaviour.

The slow development

of prefrontal structures after

birth tracks the maturation

of children into adults, and

people whose prefrontal

areas are damaged by trauma

or stroke, for example, seem

to have lost some control of

the brakes and are apt to be childishly impulsive

and uninhibited in their behaviour.

With tools such as psychological tests and

brain imaging, researchers have been finding

similar braking problems associated with drug

use and are starting to tease apart the mechanisms

involved. Some have shown that people

with drug addictions are poor at monitoring

and inhibiting impulses — and these

behavioural findings have been matched to

functional magnetic resonance imaging (fMRI)

data that show reduced activity in the corresponding

prefrontal areas. Animal studies

have supported the human ones by

showing, for example, that monkeys given

And other researchers have found

that stress, which frequently triggers drug

use and relapse in people with addiction,

seems to do so at least in part by shutting

starting to understand the molecular basis

of why this cortex falls apart with drugs of

abuse, and during stress, and how those

two interact,” says Amy Arnsten at Yale

University School of Medicine in New

Haven, Connecticut.

If the cortex falls apart with drug

abuse, then it may be impossible to

recover from an addiction without

putting it back together. In unpublished

studies, Hugh Garavan and his colleagues

at Trinity College, Dublin, have found

that cocaine users and tobacco smokers

who go through treatment and are able

to stay abstinent for more than a year

“seem to show hyperactivity in these prefrontal

control centres” in fMRI images.

Garavan says that this extra activity

seems to be especially prominent during

the first few weeks of abstinence, hinting

at “a heavy reliance on these prefrontal

centres to avoid falling off the wagon”.

The recognition that prefrontal systems might

need boosting in people with addictions has

helped fuel a new interest in whether AA and

similar behavioural treatments are already having

these kinds of effects. “It behooves us to try

to understand how [twelvestep

approaches] link to what

we’re addressing in terms of

intervention,” Volkow told

the annual meeting of the

Society for Neuroscience in

Washington DC last November.

So far, these treatment

programmes have been difficult

to study formally, says

Martin Paulus, a psychiatrist

who is researching addiction

at the University of California, San Diego. “It’s

very much a voluntary-based programme, with

little standardization, and the whole programme

thrives on anonymity.”

But much of what is known about the AA

approach suggests that it aims to protect or

enhance prefrontal circuits. In the protected

environment of a rehab centre, drugs and other

cues associated with drug taking are gone and

stressful situations that suppress prefrontal

activity are minimized. Volkow notes that the

feeling of ceding control to a higher power is

also likely to “enhance your sense of security,

decreasing stress and anxiety”. Similarly, says

Garavan, the confessions of bad behaviour and

other “strategies that push users to become more

aware of their drug-related actions presumably

aim to boost their capacity for self-monitoring,

which is largely a prefrontal function”.

The social environment in rehab is another

factor that works in part through prefrontal

systems. “Our brains have evolved to be very

sensitive to social cognition and social reinforcers,”

says Volkow. By putting people with drug

addictions into a group with anti-drug values,

“you are providing them with a very powerful

reinforcer”, she says.

And then there is religion, which has been

shown to have a strong inverse association

with drug addiction. Psychologist Michael

McCullough, who studies religion and behaviour

at the University of Miami in Florida,

calls this inverse association “one of the most

unsung findings in the entire literature on drug

and alcohol abuse”. Both adults and children

deemed religious by various measures “drink,

smoke and do drugs less often”, McCullough

says. “If they get into trouble with drinking

and drugs and smoking, they’re more likely to

be able to get away from those problems.”

McCullough suggests that when a person

commits to any cultural system that regulates

behaviour, the psychological effort to conform

strengthens the brain systems that mediate

self-monitoring and self-control. “What

makes religion unique, I think, is that the code

of conduct isn’t just laid down by your parents

or your friends or your principal at school, but

ostensibly by the individual who is superintending

the Universe, so it has an extra moral

force.” Some religious rituals, he says, have been

shown to provoke enhanced activity in prefrontal

meditation are pinpointing precisely those [prefrontal]

areas of the brain that people rely on to

control attention, to control negative emotion

and resolve mental conflict.”

However the twelve-step strategies actually

work on the brain, “there is now excellent

documentation that those who attend

AA-type programmes regularly do very well

by anyone’s standard”, says Thomas McLellan,

director of the Treatment Research

Institute in Philadelphia, Pennsylvania.

The problem, McLellan says, is that the

vast majority of people who enter such

programmes do not go regularly — they

drop out after a few days or weeks — and

are more than likely to relapse.

Anna Rose Childress, a psychiatrist at

the University of Pennsylvania School of

© 2009 Macmillan Publishers Limited. All rights reserved

Medicine in Philadelphia, has encountered

a similar resistance to treatment in the

crack cocaine users she has studied. In her

lab she uses a cognitive behavioural training

technique — like “prefrontal pushups”,

she says — that tries to make these users

more aware of their drug-related actions

and the consequences. But her studies

indicate that “most of our cocaine patients

are not great at it”.

Results such as these raise what Childress

and others call the “chicken or egg question”

— is drug use the cause of users’ prefrontal

problems, or do they have pre-existing defects

that make them susceptible to addiction? As

Garavan puts it: “A lot of people might be

able to enjoy drugs but there’s only a certain

percentage who actually go on to become

addicted. And maybe part of that is because

these people lack that prefrontal-mediated

control over behaviour.”

Some research already links prefrontalrelated

conditions such as impulsivity and

attention deficit hyperactivity disorder

(ADHD) to a heightened risk of later drug

use. But to really start answering the chicken

or egg question, says Childress, “you would

need some good large-scale developmental

studies for one thing; you would like to look at

adolescents before they’ve ever touched drugs”.

Garavan and several dozen other European

researchers are now participating in a project

that aims, in part, to do just that. Known as

IMAGEN and begun in late 2007, the five-year,

€10-million (US$14-million) project funded by

the European Commission will ultimately enrol

2,000 14-year-olds and follow them through

their late teens. Principal investigator Gunter

Schumann, a psychiatrist at Kings College, London,

says that the testing will include fMRI and

structural MRI, as well as a full genome scan.

He expects to start publishing findings in the

next few years.

In the meantime, researchers are pursuing other

ways to boost prefrontal systems — and medicines

for ADHD seem an obvious place to start.

Attention-enhancing drugs such as methylphenidate

and atomoxetine boost the activity

of key receptor systems in the prefrontal cortex,

in particular those for noradrenaline and

dopamine. Some evidence already suggests that

patients with ADHD are less likely to go on to

abuse drugs if they are receiving medication for

led by Daina Economidou at the University of

Cambridge, UK, reported that atomoxetine

helped rats with an ADHD-like impulsivity to

The National Institute on Drug Abuse has

also been supporting studies of cognitive

and behavioural strategies, and Volkow says

that she is particularly enthusiastic about

an approach that involves “real-time fMRI

feedback”. Developed by researcher and entrepreneur

Christopher deCharms earlier this

decade, the technique involves placing drug

users in an fMRI machine and showing them

a symbolic representation — a flame — of the

fMRI-measured brain activity that corresponds

to their cravings. The users are then asked to

apply their own cognitive exercises, such as

imagining their child is with them, to quench

their cravings and douse the flame. After half a

dozen sessions with this feedback the user will,

in principle, develop cognitive circuitry that is

more efficient at suppressing craving and that

can then be used in ordinary life. A version of

the technique, used for pain relief, has already

and deCharms and his Silicon Valley start-up,

Omneuron, are currently running a small trial

in smokers — with plans for a follow up with

some of Childress’s cocaine users.

For some people, even the most sophisticated

therapies may not be enough to rescue

a prefrontal cortex that has been damaged by

genetics, development and perhaps decades

of drug use. “It’s like somebody who has had

a stroke and is paralysed,” says psychologist

Antoine Bechara at the University of Southern

California, “and you tell them, well, you should

walk, you should exercise. But the part of the

brain that allows them to do that is not there

and they just cannot do it.”

To Bechara, a more efficient approach would

be to protect and strengthen these critical brain

regions as they are developing. As an example,

he cites preliminary data from a study in

China. “There are children who grow up whose

parents make all the decisions for them, and

others who are encouraged to make decisions

and are rewarded or punished for their bad

decisions,” he says. “The latter children grow

up to show better performance on measures

of decision making, and there is even a hint

of evidence from fMRI that the kids with that

latter kind of parenting style have better prefrontal

cortex function.”

Even for those beyond the influence of

parenting style, researchers hope that a

little lift in prefrontal efficiency could go a

long way. Such a boost, says Paulus, could

be “the critical piece that helps prevent the

person from getting onto a very destructive

pathway”.

The question now is how best to give that

boost. As researchers come to understand the

neural mechanisms of addiction better, the

twelve-step approach may give way to more

secular strategies. But it seems unlikely that all

behavioural approaches will soon be replaced

by a pill. “I think most researchers would say,

and I know I would say, that medicines should

be used in the context of a good behavioural

programme,” says Childress, “because a person

is essentially trying to restructure a lot of

behaviour, and the more support that you can

provide for that, the better.” ?

Jim Schnabel is a freelance writer based in

Maryland.

Archives Press, 2000).

3. Hester, R., Simões-Franklin, C. & Garavan, H.

4. Olausson, P. et al. Annl NY Acad. Sci. 1121, 610–638 (2007).5. Hains, A. B. & Arnsten, A. F.

(2008).

(2008).

j.biopsych.2008.12.008 (2009).

9. deCharms, R. C. et al. Proc. Natl Acad. Sci. USA 102,

18626–18631 (2005).

AA-type group behavioural therapy may tap into

brain regions neuroscientists think are crucial in

overcoming addiction.

S. DOERING/VISUM/STILL PICTURES J. VARNEY/SPL BSIP, LAURENT/LESACHE/SPL

NATURE|Vol 458|5 March 2009 NEWS FEATURE

© 2009 Macmillan Publishers Limited. All rights reserved