Over the next decade, new treatments are likely to include “cocktails” of two or three old drugs and possibly a treatment vaccine. Why is the drug pipeline for this major public health problem stuck at a trickle?
Recovery from substance abuse can sometimes seem like an endless talkfest: therapy sessions, support groups, 12-step meetings and the like.
Scientific advances, however, have put forward a medical model of addiction as a disease rooted less in the mind than in the brain. A new consensus is emerging that medical treatments will be the go-to for getting and staying sober, as is the case with depression in the age of Prozac. Sharing and caring in one meeting or another will remain significant supports, but combinations of psychoactive drugs or even treatment vaccines will do the heavy lifting to reclaim your “hijacked” brain from addiction.
The addiction drug pipeline has never looked so good; it has gone from a drip-drop to a trickle. But substance abusers can look forward to some new treatments over the next decade. None are likely to be a breakthrough on the order of Prozac. Like Vivitrol (naltrexone injections) for alcohol and opiate abuse, they will work well for some people but offer only modest benefits to most.
Addiction is the most neglected disease in drug development, even though it is one of the nation’s leading public health problems. Why the neglect? First, basic research into the brain mechanisms of addiction—neurotransmitters, pathways, etc.—is still full of unknowns. Second, Big Pharma, which alone has deep pockets to bring new drugs to market, has given addiction the cold shoulder, partly because many addicts are poor, uninsured, hard to reach and not especially health conscious. Nor is this highly regulated industry crazy about associating its brand with people who use illegal drugs. But at bottom the neglect stems from the pervasive social stigma of addiction, according to many top researchers.
The drug industry makes one exception: nicotine addiction. As proven by the $750 million annual sales of varenicline (Chantix), the only drug on the market to help smokers quit, drug companies are spending big bucks to back R&D for a global market made up of hundreds of millions of people. Cigarettes are, of course, legal. Dozens of experimental compounds are in clinical trials.
For all the buzz about addiction as a brain disease, treatment vaccines hold the most promise of a breakthrough—and they do not even target the brain. Like preventative vaccines that protect you against, say, the flu, treatment vaccines prime your body’s immune system to produce antibodies that recognize the invading pathogens, destroy it, and then “remember” it in the event of future exposures. But treatment vaccines, as the name suggests, help control a disease that you already have. When applied to addiction, vaccines aim to produce an immune response not to an infectious pathogen but to the substance of abuse. Treatment vaccines prevent you from getting high by preventing the molecule of cocaine, say, or heroin from reaching your brain, where it has its effects.
Vaccine research for substance abuse is appealing partly because vaccines are tried and true; they are pretty simple to make; and they do not muck around with brain processes. But there are plenty of challenges. Most drug molecules are too small for the immune system to recognize. So scientists attach other, harmless molecules to the vaccine agent (the drug molecule) in order to add bulk in order to spark an antibody response. For instance, Thomas Kostens, MD, psychiatry and neuroscience professor at Baylor College of Medicine in Houston—and a leading addiction treatment researcher—fused bits of deactivated cholera bacteria to cocaine molecules to get the attention of the immune system. Its antibodies are big fat proteins; once they glom onto the cocaine-cholera combo, the resulting conglomeration cannot pass through the blood-brain barrier. Blunting the effect of the coke would, in theory, support your effort to quit using. In 2009, Kosten’s vaccine provided the first evidence that this approach could work in people.
There are many experimental vaccines currently in test tubes and early studies of animals. Very few will make it to clinical trials in humans. So far, the most promising, like Kosten’s, have gone bust in human tests.
At the center of the addiction vaccine enterprise is the prestigious Scripps Research Institute, a private nonprofit in La Jolla, Calif. Its Committee on Neurobiology of Addictive Disorders (CNAD) has six of the nation’s top addiction scientists studying the intersection of the brain, emotion, stress and addiction; the same six are also members of Scripps’ Pearson Center for Alcoholism and Addiction Research, which “translates” CNAD’s lab discoveries into experimental treatments.
In the early 1980s, when a vaccine for addiction struck most researchers as absurd, “the stars of two research programs at Scripps aligned,” says George Koob, MD, the scientist who chairs CNAD. At the time, Koob’s lab was doing basic research, and Kim Janda, MD, was hunting for a chemical that might put a dent in cocaine addiction. When the two teams began collaborating, the synergy was “momentous.”
Since then, Janda has tried to develop vaccines against nicotine, alcohol, marijuana, heroin, cocaine and methamphetamine. His failures have blazed trails. Most recently, his experimental coke vaccine, created by cobbling together a cold virus particle and the cocaine molecule, got as far as Phase III clinical trials before failing. Yet the trial showed some success: Addicts who had the strongest immune response did not get high when they used and had a longer period of abstinence. But one-fourth of the subjects produced no antibodies to the vaccine.
Scripps presses on, producing a new vaccine candidate almost seasonally. In May, Koob’s lab announced that a heroin vaccine showed efficacy in rat studies. Each substance presents its own particular challenge to a vaccine approach. Heroin quickly breaks down in the body into two other chemicals: 6-acetylmorphine and morphine. An effective smack vaccine would have to target both at once, and the new Scripps candidate fits the bill.
Scripps is also making progress with a vaccine against methamphetamine. Meth’s particular challenge is that its active molecule’s structure is so generic that meth-primed antibodies can mistake many other molecules for it. Scripps’ Michael Taffe, PhD, and his team are testing MH6, one of six potential meth vaccines developed in Janda’s lab. In a soon-to-be-published rat study, MH6 decreased the critters’ symptoms of meth addiction.
Scripps doesn’t have a monopoly on addiction vaccine research. Baylor’s Kosten and S. Michael Owens, PhD, the head of the Center for Alcohol and Drug Abuse at the University of Arkansas for Medical Sciences, are leaders in the field. Kosten has spearheaded research into the neuroscience of addiction and trauma for decades and has studied a wide range of treatments and would-be treatments, including a cocaine vaccine, immunotherapy for hallucinogens, buprenorphine (Suboxone) for opioid dependence and disulfiram (Antabuse) for cocaine abuse.
Owens is currently in the race for a methamphetamine vaccine, with one of his anti-meth shots already in human tests for safety. Owens’ innovative approach is very different from Taffe’s more traditional one, however. Owens is synthesizing methamphetamine-primed antibodies in the lab and then injecting them into patients. Rather than waiting to see if your body produces its own antibodies, “we can give you enough antibody and we can do it fast and at the right dose, just like any other medication,” Owen says.
A major problem with all addiction vaccines is that their effect is short-lived. A decent immune response typically requires a series of injections over a month or so, but the response may fade in a matter of weeks. But to overcome addiction, many people need long-term, even lifetime, treatment. The costs and complications of a vaccine that must be administered every few months would probably be prohibitive for both patients and health insurance companies.
Ironically, Scripps’ most significant contribution to addiction treatment is not a vaccine at all but a pill that has been around for years. Researchers have shown that gabapentin (Neurontin), originally approved to treat seizures, has modest effectiveness against alcoholism during acute withdrawal and early abstinence. While vaccines prevent the substance from entering the brain, conventional drugs like gabapentin are chemicals that “block the brain effect, not just the substance effect,” Koob says.
The Center for Studies of Addiction (CSA), at the University of Pennsylvania’s School of Medicine, may be our best hope for getting effective treatments into addicts’ bodies in the near term. Because CSA not only researches new treatment options but actually works with people with substance abuse problems, they have established a unique program of clinical trials of psychoactive drugs already approved for other conditions to see if they can help curb addiction. This is one of the most economical ways to bring an addiction treatment to market. Most of these drugs have been around for years, so their safety issues are well known; they can go directly into human trials.
No one expects any of these drugs to be a game-changer. Because each will likely offer, at best, only modest benefits, CSA is banking on the “cocktail” model of treatment: Use two or three partially effective drugs together to target different receptors and pathways at the same time.
CSA’s program includes testing two medications for alcohol abuse: naltrexone, an old anti-craving drug, and Seroquel, a bipolar treatment. Trials are up and running for the dual addiction of alcohol and cocaine with a combination of naltrexone and modafinil, a non-amphetamine stimulant that has not exactly won raves in previous anti-cocaine studies. Nonetheless, CSA is doing its own modafinil-for-coke-addiction trial, adding the anti-nicotine drug Chantix. The program has a certain throw-it-against-the-wall-and-see-if-it-sticks rationale, but some of these drugs will likely stick for some addicts.
Kyle Kampman, MD, medical director of CSA’s Addiction Treatment and Medication Development Division and principal investigator of a project in the Cocaine Medication Development Center, reports that his lab just completed a trial of a cocaine vaccine (the data are still being analyzed). Substance abuse vaccines fit the “cocktail” model perfectly. Because vaccines do not affect the brain, a cocaine addict could take both the vaccine and psychoactive drugs that do target the brain; a heroin addict could do a vaccine-Suboxone cocktail. Pile on the pills!
Progress in basic research and clinical trials is slow and expensive—witness the ongoing failures of Scripps’ many experimental vaccines. Both Scripps and CSA are funded mainly by the federal government and pharmaceutical companies. But money is tight. Scripps’ Kroob says that their promising heroin vaccine is in limbo until he finds financial backers to pay for more animal studies. “This kind of money would usually come from pharma companies,” he says. “But there’s a stigma associated with working with drug addiction.”
The drug industry has calculated that the market for addiction treatments, especially vaccines, is too small to be profitable. A large number of clinicians would have to prescribe the treatment. But only some 3,500 physicians in the US specialize in addiction. Many physicians do not see addiction as a legitimate medical condition and have no interest in treating addicts. Others look at the high failure rate of all addiction therapies and recoil.
Obamacare might somewhat improve the situation. Many poor and uninsured people with substance abuse will become eligible for Medicaid. The Affordable Care Act mandates that Medicaid and all health insurance for newly eligible adults starting in 2014 must include services for substance use disorders. Yet whether the coverage offered by Medicaid and the exchanges will prove adequate remains to be seen. Medicaid has a lifetime cap for methadone and Suboxone that covers only five months of treatment. Yet controlling substance abuse with long-term medication is cost-effective. “Look at any emergency room,” Koob says. “Half of the patients are there because of addiction-related issues.”
By default, the financial burden of addiction drug research has largely fallen to the federal government, especially the National Institutes of Health (NIH). “That’s why the NIH is so important,” says Donald Vereen, MD, the director of the University of Michigan Substance Abuse Research Center. Vereen served at the NIH during the Clinton and Bush II administrations; he was also deputy drug czar. The NIH, Vereen says, often partners with pharmaceutical companies to move promising compounds through trials and to market. Indeed, buprenorphine (Suboxone) owes its success to this collaboration. (The drugmaker gets all the profits, however.) The National Institute on Drug Abuse (NIDA) also has a medication development division—a sign, Vereen says, of private industry’s neglect of the field.
“Nobody wants to work on developing drugs for addicts,” he says, echoing the sentiments of other top researchers. Why? Because of social stigma and the criminalization of substance use. In the end, these are bigger deterrents to progress than the limits of neuroscience and the cost/benefit analyses of Big Pharma.
“The lack of treatment for addicts is ultimately a civil rights issue,” Vereen says. That is not a problem that gets solved by scientists in labs.