Twelve Months of Addiction Box

(Inspired by Twelve Months of Drug Monkey)

Drug Monkey writes:

The rules for this blog meme are quite simple.
-Post the link and first sentence from the first blog entry for each month of the past year.
I originally did this meme, after seeing similar posted by Janet Stemwedel and John Lynch.

Okay, here we go:

January:

Say what you will about glutamate-gated chloride channels in the parasitic nematode Haemonchus contortus—but the one thing you probably wouldn’t say about the cellular channels in parasitic worms is that a drug capable of activating them may prove useful in the treatment of alcoholism and other addictions.

February:

Here’s a book I’m delighted to promote unabashedly.

March:

Mo Costandi at the UK Guardian expanded on his Nature article about the mechanisms that result in memory impairment when people smoke marijuana.

April:

Our latest participant in the “Five Question Interview” series is Dr. Keith Laws, professor of cognitive neuropsychology and head of research in the School of Psychology at the University of Hertfordshire, UK.

May:

I'm not a huge fan of infographics, mostly because they tend to overpromise and are often marred by factual errors.

June:

Reporting the results of published studies concerned with genetic risk factors has always been a tricky proposition.

July:

Dr. Tom McLellan, chief executive officer of the Treatment Research Institute, who served on President Obama’s healthcare reform task force, called the recent U. S. Supreme Court Decision on the Affordable Care Act “the beginning of a new era in prevention, early intervention, and office based care for patients who are not addicted—but whose drinking, smoking, and use of other substances is harming their health and compromising the effectiveness of the care they are receiving for other illnesses and conditions.

August:

Medical marijuana advocates will finally have their day in federal court, after the United States Court of Appeals for D.C. ended ten years of rebuffs by agreeing to hear oral arguments on the government’s classification of marijuana as a dangerous drug.

September:

Voters in The Netherlands may have lost their final chance to block the nationwide imposition of the wietpas, or so-called "weed pass," as the law of the land in The Netherlands next year.

October:

People who say they are addicted to marijuana tend to exhibit a characteristic withdrawal profile.

November:

Children with heavy alcohol exposure show decreased brain plasticity, according to recent research on fetal alcohol spectrum disorders (FAS) using magnetic resonance imaging (MRI) scans.

December:

When a stroke happens to anyone under the age of 55, a major suspect is drugs, specifically the stimulants—methamphetamine and cocaine.


Photo Credit: lotteryuniverse.com

Interview with Dr. Bankole Johnson of the University of Virginia

Tailoring addiction medicine to fit the disease.

(The “Five-Question Interview” series.)

25 years ago, when Dr. Bankole Johnson first began giving lectures about addiction and neurotransmitters in the brain, he had a hard time getting a hearing. That’s because 25 years ago, everybody knew what addiction was: a lack of “moral willpower.” Or, at best, some sort of psychological “impulse control” disorder.  

As a neuropharmacologist by training, and currently professor and chairman of the University of Virginia’s Department of Psychiatry and Neurobehavioral Sciences, Dr. Johnson thought otherwise, and went on make a name for himself by discovering that topiramate, a seizure drug that boosts levels of the neurotransmitter GABA, could be used in the treatment of alcoholism. “I just wasn’t a hospital-type doctor,” he once said. “I was for more intersted in research than clinical practice.” Johnson’s work was featured in the 2007 HBO series, "Addiction."

Born in Nigeria, Dr. Johnson attended the University of Oxford and received his medical degree in Glasgow, Scotland in 1982. At the time, medical understanding of addiction was poor to nonexistent. “Everything we knew—really knew—probably could be written on the back of a postage stamp,” he recalled.

Since then, Dr. Johnson has published numerous articles on psychopharmacology and addiction, and has served on several National Institutes of Health committees and panels. (See my earlier POST on Johnson’s study of drugs for addiction in the American Journal of Psychiatry.)


1. You’re a native of Nigeria. How did you first become interested in medicine?

Bankole Johnson: My father was a doctor and encouraged me. Back then, I had little interest in medicine and was more interested in the arts and perhaps going to law School, for which I had been promised a scholarship.

2. Addiction is called a “disease of the brain,” in Alan Leshner’s famous phrase, but it is still a hugely controversial subject. Are innate biological differences the cause of addiction?

Johnson: Addiction is a brain disease. The roots of the disease lie in brain abnormalities, and these are exacerbated when a vulnerable person uses alcohol excessively or takes illicit drugs.

3. How did you discover that topiramate helped some alcoholics drink less?

Johnson: It was an idea that developed from a hypothesis I came up with based on brain neurochemistry. The central idea was to alter the signals of dopamine, a critical path for the expression of rewarding behavior, through two different and opposite systems—glutamate and GABA.

4. That work led to Topamax for alcoholism, and your more recent work with ondansetron, another GABA antagonist. But what role do environmental and sociocultural factors play in the development of addiction?

Johnson: The environment interacts with genes and brain chemistry to govern behavior. But in the end, it is the changes in the brain that ultimately direct alcohol and drug taking behavior.  The environment therefore provides the context and tuning of the neurochemical signals in the brain.

5. Some people find the notion of addiction as a progressive and incurable condition a hard pill to swallow, so to speak. Why has effective medical treatment for addiction been so slow to develop, and why hasn’t talk therapy been more effective?

Johnson: Talk therapy has some effectiveness, but alone it is not a comprehensive or robust treatment. Progress in the last two decades has been quite rapid. With growing and clear acceptance of the neurobiological underpinnings of addiction, the next decade should herald even more exciting discoveries.  For example, our work on pharmacogenetics promises to provide effective medications—such as ondansetron—that we can deliver to an individual likely to be a high responder, based on his or her genetic make up.

Photo Credit: Luca DiCecco

A Few Words About Glutamate

Meet another major player in the biology of addiction.

The workhorse neurotransmitter glutamate, made from glutamine, the brain’s most abundant amino acid, has always been a tempting target for new drug development. Drugs that play off receptors for glutamate are already available, and more are in the pipeline. Drug companies have been working on new glutamate-modulating antianxiety drugs, and a glutamate-active drug called acamprosate, which works by occupying sites on glutamate (NMDA) receptors, has found limited use as a drug for alcohol withdrawal after dozens of clinical trials.

Glutamine detoxifies ammonia and combats hypoglycemia, among other things. It is also involved in carrying messages to brain regions involved with memory and learning. An excess of glutamine can cause neural damage and cell death, and it is a prime culprit in ALS, known as Lou Gehrig’s disease. In sodium salt form, as pictured---> it is monosodium glutamate, a potent food additive. About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. Drugs that boost glutamate levels in the brain can cause seizures. Glutamate does most of the damage when people have strokes.

The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. Unfortunately, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. (Dissociative drugs like PCP and ketamine are glutamate antagonists.) Dextromethorphan, the compound found in cough medicines like Robitussin and Romilar, is also a weak glutamate inhibitor. In overdose, it can induce psychotic states similar to those produced by PCP and ketamine. Ely Lilly and others have looked into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

As Jason Socrates Bardi at the Scripps Research Institute writes: "Consumption of even small amounts of alcohol increases the amount of dopamine in the nucleus accumbens area of the brain—one of the so-called ‘reward centers.’ However, it is most likely that the GABA and glutamate receptors in some of the reward centers of the basal forebrain—particularly the nucleus accumbens and the amygdala—create a system of positive reinforcement.”

Glutamate receptors, then, are the “hidden” receptors that compliment dopamine and serotonin to produce the classic “buzz” of alcohol, and to varying degrees, other addictive drugs as well. Glutamate receptors in the hippocampus may also be involved in the memory of the buzz.


Writing in The Scientist in 2002, Tom Hollon made the argument that “glutamate's role in cocaine dependence is even more central than dopamine's.” Knockout mice lacking the glutamate receptor mGluR5, engineered at GlaxoSmithKline, proved indifferent to cocaine in a study published in Nature.

In an article for Neuropsychology in 2009, Peter Kalivas of the Medical University of South Carolina and coworkers further refined the notion of glutamine-related addictive triggers: "Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking," Kalivas writes. "While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors."

The same year, in Nature Reviews: Neuroscience, Kalivas laid out his “glutamate homeostasis hypothesis of addiction.”

A failure of the prefrontal cortex to control drug-seeking behaviors can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

This kind of research has at least a chance of leading in the direction of additional candidates for anti-craving drugs, without which many addicts are never going to successfully treat their disease.


Graphics credit: http://cnunitedasia.en.made-in-china.com/

What is Drug Craving?

Exploring the engine of drug relapse.


“In terms of treatment, you can’t just attack the rewarding features of the drug. In the case of alcohol, we already have a perfect drug to make alcohol aversive--and that’s Antabuse. But people don’t take it. Why don’t they take it? Because they still crave. And so they stop taking it. You have to attack the other side, and hit the craving.”
--Dr. Ting-Kai Li, 1990 interview

It causes relapses and treatment failure. It leads good people to break good promises and do harm to themselves and others. What is this thing called craving? Isn’t it just another word for lack of will power?

Scientists have gained a much deeper understanding of how and why addicts crave. For years, craving was represented by the tortured tremors and sweaty nightmares of extreme heroin and alcohol withdrawal. Significantly, however, the symptom common to all forms of withdrawal and craving is anxiety. This prominent manifestation of craving plays out along a common set of axes: depression/dysphoria, anger/irritability, and anxiety/panic. These biochemical states are the result of the “spiraling distress” (George Koob’s term) and “incomprehensible demoralization” (AA’s term) produced by the addictive cycle. The mechanism driving this distress and demoralization is the progressive dysregulation of brain reward systems, leading to biologically based craving. The chemistry of excess drives the engine of addiction, which in turn drives the body and the brain to seek more of the drug.

Whatever the neuroscientists wanted to call it, addicts knew it as “jonesing,” from the verb “to jones,” meaning to go without, to crave, to suffer the rigors of withdrawal. Most doctors don’t get it, and neither did many of the therapists, and least of all the public policy makers. Drug craving is ineffable to the outsider.

Drug craving itself is mediated by glutamate receptor activity in the hippocampus—the seat of learning and memory. A fundamental branch of what we might dub the “relapse pathway” runs through the glutamate-rich areas of the hippocampus. The puzzling matter of craving and relapse began to come into focus only when certain researchers began to rethink the matter of memory and learning as it applies to the addictive process. This led back to the role of glutamate, and it gradually became clear that the drug high and the drug craving were, in a manner of speaking, stored in separate places in the brain. Research at the National Institute for Drug Abuse (NIDA) strongly supports the hypothesis that drug memories induced by environmental triggers originate primarily in the hippocampus. And glutamate may be the substance out of which the brain fashions “trigger” memories that lead certain addicts down the road to relapse.

Glutamate is the most common neurotransmitter in the brain. (In sodium salt form, as monosodium glutamate, it is a potent food additive.) About half of the brain’s neurons are glutamate-generating neurons. Glutamate receptors are dense in the prefrontal cortex, indicating an involvement with higher thought processes like reasoning and risk assessment. The receptor for glutamate is called the N-methyl-D-aspartate (NMDA) receptor. And unfortunately, as the gifted science writer Constance Holden related in Science 292, NMDA antagonists, which might have proven to be potent anti-craving drugs, cannot be used because they induce psychosis. Dissociative drugs like PCP and ketamine are glutamate antagonists.

However, drugs that play off receptors for glutamate are already available, and more are in the pipeline. As a precursor for the synthesis of GABA, glutamate has lately become a tempting new target for drug research. Ely Lilly and others have been looking into glutamate-modulating antianxiety drugs, which might also serve as effective anti-craving medications for abstinent drug and alcohol addicts.

Photo credit: Changing Lives Foundation