These are notes from a symposium held at the Society for Neuroscience in the fall of 2003. Participants included Drs. Nora Volko (current head of NIDA), Chuck O'Brien, Glen Hanson and Doug Marlow. It was chaired by Stephanie J. Bird of MIT.

Information about this roundtable can be found on the SFN website. I think I accurately represented what each of the speakers said, but any mistakes are mine alone.


There are four main areas of research interests regarding drug abuse: salience/reward, motivation, inhibition, and memory.

Dopamine (DA) is involved in reinforcement and salience -- and is abnormal in cases of drug abuse, especially D2-dopamine receptors. There is a decrease in D2 receptors in those individuals who are abusing cocaine, alcohol, heroin and methamphetamine (and probably others, although we currently have no data).

Dopamine is released in response to salience [perceptual prominence, or likelihood of being noticed], whether the stimulus is pleasant, aversive, unexpected or novel. Then there is reuptake of the DA within 30 seconds. The DA interacts with receptors based on the concentration of DA and the number of receptors available. So a decrease in D2 receptors in drug abusers leads to a decreased chance of recognizing salience. However, drugs of abuse generally increase DA through release or by reuptake inhibition, which leads to an even greater increased sense of salience for the drugs but a decreased salience for natural reward.

Elliot Stein has shown in his lab that there is a decreased responsivity to sex films compared to drug films in drug abusers compared to normal subjects. This has also been shown to be true for food cues. This suggests that discomfort in drug abusers is not relieved by "natural" rewards.

In drug abusers, the cingulate gyrus (CG) and the orbital frontal cortex (OFC) show reduced utilization of fluorodeoxyglucose (FDG) (i.e. decreased regional cerebral metabolic rate for glucose; rCMRglc), indicating reduced activation of those brain areas. There is also a decrease in D2 receptors in the OFC. The reduced rCMRglc and reduced D2 receptors are correlated in cocaine abusers as well as in methamphetamine abusers.

This is interesting because the OFC is where salience attribution occurs, so that this region is active when there are changes in the reinforcement value of reward (and during "stop" behavior to prevent obtaining a reward). The CG is where inhibitory control occurs. In addition, conditioned learning involves the amygdala, habit learning involves the dorsal striatum, and declarative memory involves the hippocampus.

Anna Rose Childress has shown in her lab that the conditioned associations between cocaine and craving in cocaine abusers involve the amygdala.

The prefrontal cortex and the CG act as a "stop circuit" on the drive to take drugs. This circuit is not functional in drug abusers, especially in the face of extra memory and salience associated with drug taking, which leads to a positive feedback loop.

Audience Question: When researchers work with drug abusers that fit the criteria from the DSM-IV, are they without other concurrent diagnoses?

Presenter's Answer: Yes, that is correct -- they only meet criteria for drug abuse.

The use of the term "drug dependence" in relation to drug abuse has led to pain in patients because it is often confused with physical dependence. I wish that we had used the word "addiction" when I was on the DSM-III-R committee -- and I am pushing for it as a substitute for "drug dependence" in the DSM-V. I define "addiction" as drug use that is out of control.

The most addictive drug is nicotine, where 32% of those who try it become addicted to it. For heroin, it's 23%, for cocaine, 16% and for alcohol, 15.4%.

The risks for whether a person will become addicted involve the drug used, the host, and the environment, all of which have varying competing influences. Genetics is an enormous component.

Typically, treatment follows this path: detoxification, 28 day rehab, graduation and relapse. We often forget that the brain is still addicted to drugs after detox. Relapse is the defining factor of drug abuse, even after long abstinence and knowledge of the toxic effects of the drugs.

A wide range of factors can contribute to relapse, especially conditioned responses.

The concept that addiction is memory has a long history. Pavlov spoke of it in the 1920's and Wikler spoke of it in the 1940's.

It is easier to learn things when we are kids, but much harder to learn them as adults.

Craving is a condition where an individual has a conditioned response to the cues associated with drug use that makes that person want to use drugs. The addicted brain has learned changes that facilitate relapse. There is reduced inhibition that leads a person to be unable to say no to drugs because there is decreased activity in the frontal cortex, as well as decreased grey matter.

Why do some people become addicted to drugs and some people don't? There really isn't a good answer yet.

There are three general strategies for getting a person to stop using drugs: agonist maintenance -- with or without concomitant psychotherapy, and newer anti-craving drugs. These anti-craving drugs reduce relapse, reduce desire and are not agonist substitutes -- they include such drugs as naltrexone, acamprosate, bupropion, propranolol, modafinil, baclofen, GVG, and topiramate. These drugs reduce the reports of craving and decrease activation in the brain regions that are active during drug craving.

In alcohol-preferring animals, the alcohol self-administration can be blocked with naltrexone, which also blocks the DA surge that occurs before alcohol is ingested. In humans, naltrexone blocks the high from alcohol and decreases drinking (when used in conjunction with therapy). There is relapse after naltrexone is stopped, just as there is relapse to heart disease when anti-hypertensives are stopped. The best medicine combination is naltrexone plus acamprosate.

There is a revolving door between addiction and crime. Naltrexone reduces recidivism from 56% to 26% and is especially important when given in depot form (sustained-release SR injectable formulation).

Question: What about the low relapse in physicians who are highly motivated to stop using drugs? They often can accomplish this even without intensive treatment. This complicates how the criminal justice system deals with this, doesn't it?

Answer: Smoking has the lowest success rate of any drug that people attempt to quit, but some people are able to quit on their own. Physicians use the same strategies as street addicts to be able to keep using drugs (like lying to themselves or others), yet they are more motivated than other addicts to stop using drugs because they can lose their medical license if they don't succeed at quitting. Treatment must itself become reinforcing.

Question: Will opioid addicts substitute another addictive drug if they are on naltrexone?

Answer: Yes -- especially cocaine or barbiturates/benzodiazepines. Remember, though, that treatment is never about the medication alone.

Three years ago, I didn't think that social policy was important to drug research. But now, after having been Acting Director of NIDA, I realize that social policy is important to scientists.

The American view about drug abuse is that it is one of the top health priorities. It often comes in as the number one health concern when Americans are polled, yet it plays a role in many other top health problems listed. This leads lots of folks to weigh in on drug abuse as far as what policy should be.

Drug abuse issues are emotionally charged and inform our views of what should be done in terms of criminal justice and health care.

I know a well-respected colon surgeon who had a sister who had been a methamphetamine addict since she was a teenager. He said that his sister had destroyed his parents and their family with her addiction. He felt that after decades of attempting to help her in every way possible to get off drugs, he could see his way clear to not only locking her away in jail for the rest of her life, but that he could condone capital punishment for her. This clearly indicates that the surgeon had lost his objectivity on the issue! And this illustrates that the issues are complex, even for science, but more so for policy decisions.

Drug abuse is either seen as a disease or as a morality issue. Science says that it's a disease, yet even the government uses sensationalism in their anti-drug abuse campaigns, such as the infamous "this is your brain on drugs" egg campaign. At first, some people might be drawn into the information, but quickly the campaign was discarded by the public.

The impact is that criminalization is seen as a treatment strategy, which contrasts with the use of science in the service of prevention and treatment. These two perspectives are clearly often at odds with each other.

I gave a talk in Idaho at a conference on methamphetamine use in kids. Immediately before my talk, an Attorney General from a western state gave a talk that emphasized the innocence of children in relation to drugs. I couldn't help but note that there were many law enforcement types in the audience, many of whom were packing, and as the Attorney General talked, I could see their hands inching towards their guns. Given the urgency of what the AG was saying, I could have easily seen how this situation could have led to the law enforcement types running out of the meeting room and shooting meth dealers on sight.

Yet, the AG went on to say that the solution was not just the criminal justice system. He then mentioned the Teton Dam Disaster, which was well-known out west. In this disaster, leaks were visible in the Teton Dam. At first, they sent out folks with shovels to fix the leaks with dirt. Then when that didn't work, they sent out tractors, and finally they had to send out bulldozers to keep the Dam intact. Eventually, the Dam burst, nearly killing the guy who was on bulldozer duty that day. The AG said that drug abuse is like the Dam disaster -- and we can't keep shoveling dirt to plug the leaks, we need to deal with the underlying issues. It was at this point that I was able to step in with my talk and say, yeah, science can help with this!

The role of science is to do the research and to share it with the public and with policymakers. The public pays our salaries and funds our research. They may not listen to us if they are confused, so we have to be clear.

When I was acting director of NIDA, the issue of needle exchange was on the table. We got a call from someone at another federal agency (I won't say which one) saying that they had a report on the dangers of needle exchange and that they wanted NIDA to comment on it. We got the report and it cited a single Canadian study noting that needle exchange was a bad thing. I took the report and tasked some of my people to do what they do best -- research the issue in terms of what the science told us. The NIDA review came back and noted that studies showed that needle exchange decreased HIV and other infectious diseases, increased the likelihood of treatment, and decreased overall drug use in the neighborhoods where the exchanges were allowed. We also took time to read the Canadian study and cited it in our own review -- as a study that was *supportive* of the position that needle exchange was a good thing! A week later, that other agency told us that NIDA "wasn't a team player". Well, I'm not so concerned about being a team player, because you shouldn't be playing that game.

Our obligation is to be objective and accurate. We need to be aware of politics, but also beware of it. It is very important that you don't let politics compromise you. Be reliable and be independent. If the data say something, it's critical that you go with the science, even if the White House disagrees with the conclusions that you have drawn.

Question: The criminal justice system sells the concept of "drug abuse", in contrast to alcohol use.

Answer: Yes, there is so much emotion because so many of us have personal contact with drug abuse that it clouds our views. Science can't easily get over this barrier.

Question: Did NIDA formally rebut the other agency's position on needle exchange?

Answer: We have to pick our battles. HHS must be responsive to the policy makers. This might not be the political structure I want, but it's what we have. I told the other agency that NIDA could not endorse their position, but there was no public contradiction -- and in fact it would not have been politically appropriate to do so under these conditions where it was another agency's report.

(note that numbers may not be accurately reported in this summary because of the brevity of their discussion during the talk -- read them for their general impact)

Science does not permeate the criminal justice system.

Eighty percent of prisoners are "drug involved" -- although this may be an artifact of the criminalization of drug possession itself. However, 33% of federal prisoners and 67-75% of state prisoners were high when they were arrested. More than 50% of drug use is involvement with violence crime, domestic abuse, child abuse, etc. For pre-trial felony drug offenders, 6% are alcohol-dependent or alcohol abusers, while 39% are drug dependent.

There is a range of methods that the criminal justice system deals with drug abusers in terms of attempting to get them to stop using drugs:

Coercion without treatment -- 67% are re-arrested, 50% are then convicted and 95% return to drug use at the level they had prior to imprisonment. So this doesn't work as a treatment plan.

Intermediate sanctions (boot camp, anklets, home detention) -- either these options have no effect or people end up doing worse -- although this may be an artifact of merely observing the prisoners more closely.

Probation/parole -- 50-70% don't comply with the treatment conditions.

Treatment without coercion -- this is based on the idea that drug abuse is a disease, but 50-67% don't show up for intake, and 40-80% drop out within 3 months (it's possible that 3 months may be the minimum amount of time that is needed before results are seen) -- 90% drop out within one year and if they continue for longer than a year, there is only a 50% chance for long term abstention.

Treatment Alternatives to Street Crime (or Safer Communities, as it's been renamed) = TASC -- focuses on case managers and had better retention, but mixed outcomes, which again may be an artifact of greater monitoring of the offenders.

Captive treatment -- treatment in prison -- this has a very small effect on recidivism and has no effect on drug use because there is no follow-up when the prisoner is released. However, these programs do reduce disciplinary problems while incarcerated and they subjects are more likely to at least show up for treatment.

Civil commitment in hospitals -- this is rare now -- but it used to be in the form of "narcotic farms" (like the one the Addiction Research Center ran -- note these were not actual farms!) or hospital programs in the 1970's. However, some 70% signed themselves out when that was a possibility and 95% started using again within a year.

Punishing people may feel good, but it has no effect on drug use and doesn't change brain chemistry. Coercion alone and treatment alone don't work and captive treatment doesn't last.

Leveraged treatment -- Herb Kleber talks about this in terms of "captive treatment works as well as voluntary treatment as long as it's voluntary (i.e. the individual gets to choose to go into the program). An individual may be motivated by aversive consequences, yet entering a program may hold these problems in abeyance (such as going to jail). There is a step-wise approach for escape with close monitoring of behavior. There needs to be graduated rewards, because individuals generally are not willing to wait 12 months for the one big payoff of having their records expunged.

Drug courts -- these are a big deal now, and are similar in many ways to leveraged treatment. Participants must be non-violent offenders and can have their records expunged and time served worked out. The programs are under judicial supervision, which effectively means that the judge is head of the treatment team. The person must first plead guilty to that if they fail in treatment, they immediately get thrown in jail. 60% of those who enter complete more than 12 months of treatment and there is a 10-30% decrease in recidivism. However, it's unclear if this figure holds for those who are addicted, since many who participate were merely using drugs. It might be important to also add medications to this program.

Question: What about the proposal of Mark Kleiman to have treatment with coercion?

Answer: This is essentially what drug courts are, although the punishments are different.

Question: The problem is that drug *use* is an illegal act itself -- what about decriminalization? We allow society to use cars despite the fact that many people kill themselves or others with cars.

Answer:

(Volkow) Nicotine is the most addictive drug, not because of the neurobiology but because of the availability of the drug and the route of administration. Smoking immediately brings the drug to the brain, so smoking nicotine is similar to smoking crack cocaine. More availability of a drug in society means that more people will consume it and therefore that it will be dangerous to more people.

(O'Brien) Science must avoid bumpersticker solutions. We shouldn't talk about decriminalization for all drugs because they all act differently. I'd bet society will change its attitude to marijuana because of grassroots efforts and come to see that it's not in the same class as cocaine or heroin. The National Academy of Sciences in the 1980's recommended that each state decide how to deal with marijuana. That report was denounced and buried by the Reagan Administration -- few copies were ever published and there was a foreword by the leadership of the NAS saying that the report did not reflect their opinions.

(Hanson) Once the genie is out of the bottle, it's very hard to get it back in -- as we see with alcohol and tobacco. So we could expect to see the same level of deaths from marijuana as there is from tobacco if marijuana was legally available (there are 400,000 deaths/yr from cigarettes). Many citizens take direction for how they should behave or think about drug from the laws -- so that they reason that if it's illegal, they should stay away, but if it's legal, it's safe enough to use. But if a person never tries a drug, they will never end up having a problem with that drug. {Note that this position is consistent with Dr. Hanson's deep commitment to Mormon values.}

(Marlow) We must take into account the effect of jail on the individual when assessing what will benefit that person therapeutically.

(Volkow) There is no evidence to show whether marijuana is or is not toxic yet the question of how it affects the reward system similar to other drugs of abuse. Smoking marijuana correlates to a lack of achievement rather than a problem of working memory -- it's more about motivation. We need to emphasize the effects on the developing brain. We are currently preparing materials for "NIDA Goes to Jail" for judges -- and we are setting up 7 centers in the US for a criminal justice network for research. We want to integrate into criminal justice conferences as well.

(Marlow) There is poor evidence that 12-step programs work cos there is no controls to show comparisons, but the longer that a person stays in aftercare, the better.

(O'Brien) Alcoholics Anonymous is one of the best American inventions, but it isn't a treatment, it's a self-help group. It's good, but you still need treatment. But because there are no records, no research on AA is possible.

(Hanson) An uneven drug policy is the price we pay for a democratic society. The genie is already out of the bottle for many drugs, and we don't want to increase the problems we already have. But policy is moving because of the input of science -- look at how few places now allow smoking tobacco in public.

Question: What about how pain patients are afraid to use opioid analgesics because they are afraid of becoming addicted?

Answer: (Hanson) Molecules are neither good or bad. There is therapeutic potential for all drugs of abuse, but self-administration is a difficult issue if the drug is unsafe or addictive. It's an issue of consequences and regulations. We have to understand the pharmacology of a drug as well as its uses.