NIDA’s Volkow Defends New Medications for Addiction

On Big Data, Big Vaccines, and a Big New Agency.

In her Director’s Report to the 2011 meeting of the College on Problems of Drug Dependence in San Diego last week, Dr. Nora Volkow, director of the National Institute on Drug Abuse, sought to refute allegations that NIDA lately has been too focused on pharmacological approaches to treating addiction—“magic bullets” in the form of pills or vaccines. Dr. Volkow presented figures showing, as the CPDD Community Website reported, that “NIDA funding allocation for new medication development has remained stable at about 12% for some time, despite concerns expressed by some researchers that funding in other areas is being sacrificed to support the medication development portfolio.” Basic and clinical neuroscience research accounts for 45% of expenditures, she said.

In other news, Volkow expressed her avid interest in the possibilities presented by so-called “big dataset science”—the act of pooling together huge amounts of data in order to generate greater statistical power. She traced a set of disciplines—genetics, epigenetics, proteomics, brain imaging, clinical data, and systems biology—and said that the NIH’s Working Group on Data and Informatics  was seeking systematic ways of integrating and analyzing large biomedical datasets in these crucial areas.

As for treatment, the current emphasis is on stimulants. Volkow said that work continues on finding reliable antagonist drugs to combat the dopamine disruptions promoted by active drug abuse. She suggested that work on buspirone, the D3 receptor antagonist and partial serotonin 5HT agonist used to treat generalized anxiety disorder, has shown that it may reduce cocaine self-administration in rhesus monkeys. This would be of considerable clinical interest, since addiction medicine presently has no effective drug treatments to offer for stimulants like cocaine and methamphetamine. A large clinical study now underway is showing that buspirone blocked D3 receptors in monkey brains in a way that reduced their interest in cocaine.

And she referred to the failed promise of NicVax, the short-lived vaccine for cigarette addiction. The treatment “failed to meet the primary endpoint in Phase II trials.” In other words, it flunked out. Only 30% of addicted smokers developed sufficient antibodies from NicVax to do them any good. But she cited new research on an alternative approach to vaccines, including a new cocaine vaccine (dAd5GNE) shown to be effective in reducing cocaine addiction-related behaviors in rats through the long-term blockade of dopamine transporters.

In a related approach to producing a reliable anti-cocaine antibody, researchers in the Department of Genetic Medicine at Weill Cornell Medical College went to work on “an adeno-associated virus (AAV) gene transfer vector as the delivery vehicle to persistently express an anti-cocaine monoclonal antibody in vivo, which would sequester cocaine in the blood, preventing access to cognate receptors in the brain.” An AAV is a small virus that is infectious but not pathogenic in humans. You might have it right now, but wouldn’t know it, since AAV doesn’t cause disease. So, the researchers used an AAV to build a transporter mechanism for their monoclonal antibody, GNC92H2. In mice, the result was “persistent serum levels of high-affinity, cocaine-specific antibodies that sequestered intravenously administered cocaine in the blood.”

And finally, while the name is still up in the air, a new national institute combining the study of alcohol and the study of all other addictive drugs will follow after final recommendations submitted to NIH Director by year’s end. Volkow briefly laid out the timeline of the merger for the assembled scientists. Call it the Institute for Substance Use Disorders, or the Institute for Addiction Disorders, or the National Institute of Substance Abuse, but whatever the eventual name, it will be fully operational by late 2013, or at least that’s the plan—and Nora Volkow, the current director of the NIDA, which will merge with, or rather absorb, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), won’t be its director (See "NIH Turf Wars"). Whether that’s good or bad is the subject of much debate, but the project marches on, and seems sensible in the end.

A Shot for Cigarette Addiction?

NIDA’s Nora Volkow on addiction vaccines.

Nora Volkow, director of the National Institute on Drug Abuse (NIDA), predicted in a telephone interview on Friday that a vaccine for cigarettes could be available in as little as three years, if two large ongoing Phase 3 trials—the last major FDA hurdle—prove as successful as earlier studies.

NicVax (Nicotine Conjugate Vaccine) from Nabi Biopharmaceuticals, with a boost from a $40 million up-front cash infusion from GlaxoSmithKline Biologicals SA, is poised to become the first of a new kind of science-based addiction treatment—an avenue of approach that brings with it great promise, and a significant number of problems.

I asked Dr. Volkow if the NicVax studies had shown evidence that the effects could be overcome with greater levels of smoking. This is a hurdle that has plagued early research on a promising cocaine vaccine, as reported in the Archives of General Psychiatry (See my post "Cocaine Vaccine Hits Snag").  In the cocaine studies, researchers found that users could overcome the blunting effects of cocaine antibodies by ingesting as much as ten times their normal level of cocaine—clearly a dangerous outcome that could enhance the possibility of lethal overdose.  (See discussions at Neurotopia  and DrugMonkey).

“I am very sensitive to that issue,” Volkow said during a conference call from NIDA's Eighth Annual Blending Conference in Albuquerque, NM, where she was a featured speaker. “But the data we have give no evidence that smokers increase their cigarettes to overcome the antibodies. It was that piece of the data that led me to approve funding.”

In fact, said Volkow, “craving decreased after these vaccinations, so we would not necessarily expect smokers to try to overcome the effects. We’ve also seen a dramatic decrease in cocaine administration in animal models.” The matter of defeating a vaccine by overindulging remains a theoretical rather than an established risk, Volkow believes. 

Vaccines may operate somewhat differently that we think, she explained, by helping to extinguish the conditioned responses to craving cues as well. “We did not expect to see [anti-craving effects],” she said. “Craving is a product of memory, associated stimuli, the anticipation of a pleasant response. With cigarettes, if you feel nothing, the brain mechanism of conditioning that drives craving starts to weaken.”

The vaccine itself “is not totally stopping all of the drug from getting into the brain. But it affects the pharmacological properties, so users don’t get the expected outcome.  Nobody knows exactly how this might accelerate the extinction process—we haven’t done the studies. It’s going to be intriguing to have a product that has the capacity to make extinction much more universal.”

Volkow admitted that “we need to get a wider response,” since a significant number of smokers and cocaine users do not form antibodies from the vaccines. In addition, “we need longer-lasting responses so we don’t have to re-vaccinate.” The cocaine vaccine under study is in Phase 2 trials, and it will be several years before more definitive results are in.

The Blending Conference Volkow was attending was titled “Blending Addiction Science and Practice: Evidence-Based Treatment and Prevention in Diverse Populations and Settings.” Despite her emphasis on science-based treatments, Volkow stated firmly that social intervention and psychological treatment can be equally important, and characterized the supposed line between physical addiction and psychological addiction as an “obsolete distinction.” It is important to remember, she said, that “psychosocial interventions make biological changes in the brain” as well.

“People are desperate, and vaccines will be very helpful to those who develop antibodies. People want these magic bullets, but we don’t yet know how these vaccines will effect the therapeutic landscape.”

Graphics Credit: http://www.attcnetwork.org/

Cocaine Vaccine Hits Snag

Some addicts risk OD to overcome its effects.

The National Institute on Drug Abuse (NIDA) has increasingly placed its bets on treating cocaine addiction with a vaccine rather than an anti-craving medication. And there is reason for this: No prominent candidates for anti-craving drug treatments have yet emerged from the research on cocaine and methamphetamine addiction.

However, there’s a catch: Some cocaine addicts appear willing to risk overdose in order to defeat a new cocaine vaccine, a recent study has shown.

The study, which appeared in the Archives of General Psychiatry, demonstrated that the TA-CD vaccine could blunt the effects of cocaine in some, but not all, patients. The vaccine works by causing the production of antibodies, which attach themselves to cocaine molecules, making the molecules too big too pass effectively through the blood-brain barrier.

Of 115 addicts involved in the study, only 38 % produced sufficient antibodies to dull the effects of cocaine, Rachel Saslow of the Washington Post  reported. And among the high-antibodies group, only 53 % stayed free of cocaine 50 % of the time. “Immunization did not achieve complete abstinence from cocaine use,” said Thomas Kosten of Baylor college of Medicine, one of the authors of the paper.

Moreover, in some of the study participants for whom antibodies made cocaine a disappointing high, researchers found cocaine levels in the body to be as much as ten times higher than previous levels of usage—an obvious attempt to overcome the vaccine’s effectiveness. There were no overdoses, according to Kosten.

No researcher has claimed this as a complete breakthrough, in light of the fact that even those who responded well in the high-antibody group achieved a substantial reduction in cocaine use during the study period--but not abstinence. At this stage the work appears to be aimed more at dose reduction.

Despite the mixed results, NIDA director Nora Volkow characterized the work as “a promising step toward an effective medical treatment for cocaine addiction,” with the proviso that “larger follow-up studies confirm its safety and efficacy.” In an earlier interview with Addiction Inbox, Volkow also expressed excitement about another possible addiction vaccine: “Currently there are anti-nicotine vaccines in clinical testing, which are designed to capture the nicotine molecules while still in the bloodstream, thus blocking their entry in to the brain and inhibiting their behavioral effects. They appear to be effective in helping subjects who develop a high antibody response sustain abstinence over long periods of time. Even those people with a less robust antibody response to the vaccine, decreased their tobacco use. So this approach appears very promising.”

An earlier study by Margaret Haney and others at Columbian University Medical Center, published in Biological Psychiatry, had similar results: “The TA-CD vaccine substantially decreased smoked cocaine's intoxicating effects in those generating sufficient antibody.”

In both studies, roughly a quarter of participants made almost no antibodies at all in response to a vaccine injection.

A multi-site clinical trial of the vaccine, headed up by Kosten at Baylor, will begin sometime this spring.

Haney of Columbia told the Washington Post that people “have a mistaken view of how a vaccine might work, thinking of it as magic, where what it’s doing, at best, is blunting the effects. They get very excited, and it’s heartbreaking.” An earlier Addiction Inbox post on cocaine vaccination brought several emails from people asking where they could obtain the vaccine.

DrugMonkey at scienceblogs.com dissected the complicated study, particularly the different levels of antibodies generated in study participants, calling the vaccine “quite obviously not a silver bullet at present.” Furthermore: “Even for the high-responders the outcome was far from overwhelming, a 10 percentage improvement from 35% to 45% cocaine-free urines.” 

Given how intractable to treatment addiction to stimulants has proven, any promising results at all are cause for cautious optimism. DrugMonkey writes: “We need new approaches and this immunopharmacotherapy stuff has potential.”

Photo Credit: http://addictions.about.com/b/2009/10/10/new-cocaine-vaccine.htm