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New treatments for addiction are urgently needed. Substance use disorders are a chronic and serious health problem for many people, while relapse rates—even with current medications—are 60 to 80 percent at the end of the first year after attempting to get sober. This situation is in part due to the enduring stigma associated with addiction, even among doctors and researchers at universities and in pharmaceutical companies. But anti-“addict” prejudice is not the highest hurdle. The immense complexity of the brain (and its functions and dysfunctions) has kept neuroscience in almost a perpetual state of infancy.
Addiction with cocaine or methamphetamine may be the substance disorders most in need of movement. While there are many clinical trials underway that are looking at using existing medications in an off-label fashion, there are currently no medications specifically approved for either stimulant.
Cocaine dependence is very difficult to treat because it doesn’t really have a discrete target for pharmaceutical intervention—likewise with methamphetamine…-Dr. Kyle Kampman
“Cocaine dependence is very difficult to treat because it doesn’t really have a discrete target for pharmaceutical intervention—likewise with methamphetamine,” says Dr. Kyle Kampman, a physician and professor of psychiatry at the University of Pennsylvania and medical director of the Charles O’Brien Center for Addiction Treatment. Because both drugs use multiple pathways in the brain to produce their effects, no single compound is likely to be able to exert sufficient control over the entire mechanism.
In addition, “you change the brain with chronic use,” says NIDA’s Dr. Jamie Biswas, who is a member of the Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMCDA). This makes developing effective therapies even more challenging.
The good news is, scientists have been working on developing treatments for decades—and therefore have already made the fundamental mistakes that tend to snag progress. The bad news is, none of the experimental therapies currently under way will be a magic bullet. “No one thinks they will be a stand-alone treatment,” says Dr. Michael Owens, director of the Center for Alcohol and Drug Abuse Prevention at the University of Arkansas and the chief scientific officer at InterveXion Therapeutics, a Little Rock-based company running safety trials for an anti-methamphetamine monoclonal antibody. “You’re going to have to use these medicines in combination with therapy.”
Related Reading: What Medications Can Help You Get Sober?
Drugs to treat substance use disorders fall into one of two categories, says Dr. David A. Gorelick, who is affiliated with NIDA and the University of Maryland Medical School: the pharmacodynamic and the pharmacokinetic. Pharmacodynamic drugs work at the site of action in the brain, while pharmacokinetic drugs work before the substance has reached the brain.
All of the current FDA-approved medications for addiction are in the “dynamic” category. Two of their most common mechanisms of action are either as “receptor antagonists” or as “receptor agonists.” Both work by targeting—and blocking—the same brain receptors that the substance targets; this prevents or reduces the substance’s effect. But antagonists turn off the receptors, while agonists turn them on. For instance, the opioid receptor antagonist naltrexone helps blunt the “high” from alcohol or opioids by inhibiting opiate receptors. By contrast, opioid replacement medications like methadone block opiate receptors by activating them, decreasing the symptoms of opiate withdrawal and craving.
Both work by targeting—and blocking—the same brain receptors that the substance targets; this prevents or reduces the substance’s effect. But antagonists turn off the receptors, while agonists turn them on.
To further complicate the issue, the opioid substitution therapy Suboxone, or buprenorphine, has a mixed agonist-antagonist mechanism of action. And the anti-smoking treatment varenicline (Chantix) is a nicotinic receptor partial agonist—it stimulates nicotine receptors, but more weakly than nicotine does.
Pharmacokinetic drugs, on the other hand, work before the substance reaches the brain. This category includes immune-based therapies like vaccines and monoclonal antibodies that break down the substance while it is still in the bloodstream and before it crosses the blood-brain barrier. This is where some of the newest experimental treatments are headed, Gorelick says.
For more than three decades scientists have known that the brain chemical dopamine plays a significant role in the addiction process; for almost as long, treatment researchers have focused on it, although they have little to show for it. However, some compounds in development are making headway, Kampman notes, including dopamine transport blockers (DTBs), dopamine receptor antagonists (DRAs) and dopamine enzyme inhibitors (DEIs). Each targets a different aspect of dopamine.
Dopamine transport blockers block the transport, or “reuptake,” of dopamine from one neuron to another, thereby increasing the amount of dopamine in the receptor. Many DTBs were originally developed to treat depression, one of the most lucrative “disease markets.” But Prozac and other reuptake inhibitors that target serotonin (rather than dopamine) have filled that niche, and as a result DTBs have been aimed at addiction, but without success.
A case in point is the compound NS-2359, a triple reuptake inhibitor that works on dopamine, serotonin and norepinephrine to keep levels of all three of these neurotransmitters high. After failing in Phase II trials for depression, it was explored in alcohol and cocaine addiction for more than a decade. A trial with cocaine-experienced individuals, however, went bust.
“We’ve looked at many triple reuptake inhibitors, and we haven’t seen much success clinically,” Biswas says. Gorelick agrees: “Numerous clinically used and experimental reuptake blockers have been studied, but none are clinically useful in addiction.”
A major challenge to conducting trials for substance use disorders is making sure patients are taking the medication (at the prescribed doses and times). Additionally, the FDA demands abstinence as a measure of efficacy. Biswas believes that this is unrealistic and counterproductive. Instead the endpoints should be “improvement in quality of life—[to] get off the drug long enough that you could get a job, for example, and maintain a stable family life,” she says.
Related Reading: Why Can’t Antidepressants and Recovery Go Together?
Most experimental dopamine receptor blockers for addiction target the D3 receptor in particular. A host of these D3-specific compounds are in early-stage development for nicotine, cocaine, alcohol, methamphetamine or heroin; these include SB-277011A, SB-414796, Compound 35 and NGB 2904. “[The DRAs] might turn out to be something useful,” Biswas says, adding that it could take 20 years to go from promising animal studies to FDA approval.
The most promising dopamine enzyme inhibitor is nepicastat, aka SYN117, which targets the enzyme beta-hydroxylase—the same mechanism of action as is targeted by disulfiram, which is approved to treat alcoholism. While disulfiram was modestly successful in several controlled clinical trials for cocaine, Gorelick says, “efficacy varies somewhat with genotype of the patient, a current area of research.”
Blocking dopamine beta-hydroxylase both increases levels of dopamine, reducing the craving for cocaine, and decreases levels of norepinephrine, reducing the pleasurable responses to cocaine and the potential for relapsing under stressful situations. The Finnish biotech Biotie Therapies has partnered with NIDA to test nepicastat in a Phase II study for cocaine addicts, with results expected early this year.
“Treatment research has now expanded to other neurotransmitter targets, such as glutamate and the endocannabinoids,” Gorelick says. These include drugs that were approved for other medical conditions, such as glutamate-enhancers like N-acetylcysteine and modafinil, and GABAergic medications, like topiramate, which target endocannabinoids. New treatment modalities are also being explored, such as transcranial magnetic stimulation (TMS).
The experimental addiction treatments with the highest profile of all are vaccines. Like other pharmacokinetic therapies, vaccines target the substance while it is still in the bloodstream, blocking or reducing its passage into the brain. But for all the bark, there has been little bite so far.
“Vaccines against nicotine and cocaine have been in clinical trials, but have not been as effective as hoped for, largely because of difficulty in evoking a sufficiently large antibody response,” Gorelick says.
Vaccines are injected into the body and then trigger the immune system to produce antibodies. By contrast, another type of pharmacokinetic, the monoclonal antibodies, (mAbs), are antibodies produced in the lab and then injected into a patient. These have been developed against cocaine, amphetamine, PCP and heroin; they are effective in animals, but not yet tested in people, she says.
Vaccines against nicotine and cocaine have been in clinical trials, but have not been as effective as hoped for, largely because of difficulty in evoking a sufficiently large antibody response.-Dr. David A. Gorelick
One of the most promising new compounds for meth addiction is a monoclonal antibody. In development by InterveXion Therapeutics, Ch-mAb7F9 aims not to prevent a full-blown relapse—“people will relapse, that’s sort of a given,” Dr. Michael Owens says—but to blunt the drug’s effect and thereby help you reduce or stop your use. “The problem with meth is that it has multiple effects, so there’s no single site that you can target,” Owens says. “It makes sense to use an antibody that binds at high affinity—the [entire] addictive drug is the target.” InterveXion is doing a safety trial for a monoclonal antibody to meth—the first step in a decade-long haul toward potential FDA approval.
As with all medications and vaccines, there are drawbacks to these new experimental therapies. “For the pharmacodynamic therapies, actions on non-targeted organs or cells, which produce side effects, have kept many compounds from being clinically useful medications,” Gorelick says. “That is one advantage of pharmacokinetic treatment, which doesn’t require a target.”
While pharmacokinetic therapies may offer fewer side effects, they do have a downside: They are useless against multidrug use. A person on a vaccine for cocaine can switch to meth, say, and still get high. And unlike pharmacodynamic replacement therapies, these drugs also do not reduce cravings or withdrawal symptoms.
Gorelick believes that monoclonal antibodies may eventually play a role in treating overdoses, but efficacy trials are at least half a decade away. As for vaccines, “they are unlikely to enter routine clinical practice within the next five years,” she says.
The most realistic approach to the future of addiction treatment is probably one of modest and incremental improvements. “I don’t think we’re looking at one, but at some, of these antibodies combined with other treatments,” Owens says. “If we could help a significant percentage of the population to live with their addiction better [rather than ‘cure’ it], that would be success.”
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