A widely prescribed medication for high blood pressure could help people beat drug and alcohol addiction, according to new research from The University of Texas.
The medication, isradipine, stopped cravings for cocaine and alcohol in the university’s studies with addicted rats. After taking high-dose isradipine, the rats no longer preferred places that they previously associated with their addiction. Researchers say isradipine appears to erase the memory of sensory cues and the feeling associated with drug-taking, so that common triggers for addiction relapse and craving no longer have any influence.
“I would say isradipine has the potential to cure a critical component of addiction, which means one would not have to keep taking it once it reversed the underlying mechanism,” says Hitoshi Morikawa, M.D., Ph.D., the study’s lead researcher and an associate professor of neuroscience at The University of Texas at Austin.
The study was published in June 2015 in Molecular Psychiatry, a peer-reviewed scientific journal.
If proven effective in humans, isradipine could have a major impact on addiction recovery. An estimated 23 million Americans need treatment for drug and alcohol addiction, according to the 2013 National Survey on Drug Use and Health (most recent figures available). Relapse is one of the greatest challenges to addiction recovery; nearly half of all rehab patients experience at least one relapse within the first year of treatment.
“This study is very exciting,” says Gail D’Onofrio, M.D., Professor and Chair of the Department of Emergency Medicine at Yale University School of Medicine and a founding member of the American Board of Addiction Medicine. “It offers an opportunity to add a relatively safe pharmacological agent, already approved by the FDA, to our treatment of drug addiction.”
D’Onofrio notes that isradipine’s ability to disrupt drug-associated cues – which often contribute to craving and relapse – is “a major step forward for the treatment of addiction, known for its chronic and relapsing nature.”
Erasing the Urge to Get High
Like Pavlov’s Dog, A Conditional Response
Drug relapse typically occurs when someone in recovery faces powerful sensory cues – such as walking past a bar and feeling the urge to drink. The desire to stay clean and sober competes with the addicted brain, which has been conditioned time after time to associate certain places, people and experiences with a drug’s euphoric rush.
It’s the same conditioning principle first discovered in the famous “Pavlov’s dogs” experiments. Russian physiologist Ivan Pavlov noticed that his dogs began to salivate whenever an assistant in a lab coat entered the room, since the dogs associated the lab coats with being fed.
Intrigued by this type of conditional learning, Pavlov trained his dogs to salivate at the click of a metronome or the sound of a buzzer that had become associated with food. The dogs drooled at these sounds even when food was no longer present (contrary to popular belief, historians say Pavlov never used a bell).
Morikawa’s research applies a kind of reverse Pavlovian conditioning to addiction. In his studies, about 200 rats were trained to associate either a white room or black room with the use of a drug (alcohol or cocaine). When given a choice, the addicted rats nearly always chose the room they associated with their addiction, Morikawa says. Days later, his research team administered high doses of isradipine to the addicted rats.
The results were remarkable. The rats still showed a preference for the room with alcohol or cocaine on the first day of isradipine treatment, but no longer after that – even without isradipine treatment. Their sensory cues were reversed, and the conditioned response was “unlearned.” The sight and smell of drugs had no effect on relapse; in essence, the rats became “de-addicted” to those cues.
“I would say that isradipine worked in pretty much all rats tested, although to a varying degree. It was quite reliable,” Morikawa says.
Applied to humans, isradipine may prevent people from slipping back into addiction, even when exposed to old habits and drug-related associations.
“That’s the idea. Old cocaine buddies would not cause cravings,” Morikawa says.
The Process of Unlearning Memories
Sold under the brand name Dynacirc, isradipine is in a class of anti-hypertensive drugs known as calcium channel blockers. These inhibit the movement of calcium ions in the heart and blood vessels – which reduces stress on the heart and arteries and helps lower high blood pressure.
Calcium ion channels are also present in brain cells that are critical for reward learning, Morikawa notes. High-dose isradipine blocks these calcium ions in the reward/pleasure center of the brain, resulting in a reversal or “unlearning” of memories that are associated with addiction. Memories are not just suppressed but eliminated, according to the study results. “It basically reverses the memory of the goodness of cues related to rewards – food, addictive drugs, etc.,” Morikawa says.
The findings are significant, according to a scientist from the National Institute on Drug Abuse, which co-sponsored The University of Texas study along with the National Institute on Alcohol Abuse and Alcoholism.
“For several years now, evidence has been mounting to suggest that memories—and the mechanisms by which memories are consolidated—are an important aspect of identifying new ways to combat drug addiction,” says Joni Rutter, Ph.D., Director of the Division of Basic Neuroscience and Behavioral Research at the National Institute on Drug Abuse.
“This study provides further evidence to this: if the neurobiological processes underlying memory formation could be prevented or reversed by targeted interventions, it might be possible to extinguish the drug memory for a longer period of time.” Rutter says isradipine treatment may prevent drug cravings by overwriting or unlearning the memories triggered by strong environmental cues.
More Effective Than Suboxone, Other Medications?
In recent years, the breakthrough in addiction treatment has been the use of medications such as Suboxone (buprenorphine) for opioid dependence and Vivitrol (naltrexone) for alcohol dependence. These and other medication-assisted therapies have been shown to block the euphoric “high” after ingesting drugs, and to reduce cravings and withdrawal symptoms.
Isradipine could be much more effective, researchers say, because drug relapse is prevented entirely, as sensory triggers are nullified.
Currently there are no medication therapies to treat cocaine addiction, but a vaccine that would prevent cocaine from reaching the brain is in development. If isradipine is proven effective in humans, cocaine users may find they don’t want cocaine in the first place.
“Isradipine works by a completely different mechanism,” than a cocaine vaccine, Morikawa says. “It wouldn’t block the action of addictive drugs at all. It simply eliminates cue memory and prevents cue-induced craving in the future.”
Challenges With Isradipine
Since isradipine is designed to treat high blood pressure, there are challenges in using this medication for addiction treatment.
“One would probably have to take high dosage of isradipine – higher than the daily dosage for hypertension – so it will surely lower blood pressure,” Morikawa notes. Certain additional drugs may be needed to maintain blood pressure, but Morikawa says that’s only a short-term issue, based on the research results.
“You don’t have to keep taking isradipine. The idea is to take high dose isradipine, then one needs to get exposed to those drug-associated cues when the isradipine concentration is high in the brain, probably within a couple of hours,” he says.
Isradipine appears to erase only those unconscious memories related to addiction, when paired with sensory cues that could trigger a drug or alcohol relapse, Morikawa says. “To my knowledge, it would not reverse other memories. But one needs to be careful where to go and what to get exposed to after taking high-dose isradipine.”
The rats in Morikawa’s study were conditioned with cocaine or alcohol for just three days, but human addiction is more complex. “Real addicts are more heavily conditioned. So it is probably necessary to take isradipine and get exposed to the drug-associated cues multiple times, although in our study one exposure was enough,” Morikawa says.
While the medication shows promise for drug relapse prevention, isradipine may not help someone with a mental health disorder who uses drugs to self-medicate, Morikawa says. And it’s not a cure for physical dependence (such as withdrawal symptoms, tremors or growing tolerance for drugs) that often accompanies addiction.
“We need to keep in mind that isradipine will have no effect on physical dependence. But physical dependence is usually treatable in a detox center,” Morikawa says. “It’s the cue-induced craving and relapse that does not go away” and which isradipine targets.
Next Steps
More research is needed before isradipine can be applied to people with substance use disorders, experts say.
“With the encouraging preliminary results presented, among the next steps will be to validate this work in other preclinical rodent models of relapse, compare its actions on natural rewards, and to assess the utility in a clinical setting,” says Rutter of the National Institute on Drug Abuse. She notes that two clinical trials are underway to test isradipine for opioid addiction.
Since the Food and Drug Administration has already approved isradipine for hypertension, human clinical trials to assess the University of Texas’ studies could begin sooner than for those involving non-approved drugs, Morikawa says.
“There is a long way to go from animal studies to clinical trials,” he notes. “But isradipine is already used in people (FDA-approved), so the hurdle is lower.”