Can Israeli Scientists Help Cure Cocaine Addiction?

The brain gets particularly messed up during withdrawal, it turns out. That’s where the new field of epigenetics comes in.

Tomer Appelbaum

Prof. Gal Yadid of Bar-Ilan University has an alluring idea.

“What if I told you I have a substance that can erase from the brain addiction to cocaine — a substance that does a restart to the brain, and the addicted person no longer suffers from withdrawal symptoms?”

Yadid, a neuropsychopharmacologist, has been researching such things for years. But his latest efforts portend a possible breakthrough against drug addiction, one of the greatest challenges of brain research.

“Forty percent of people who use cocaine will never get addicted,” says Yadid, whose research has been published in the Journal of Neuroscience and Addiction Biology. “The problem is with those who get addicted and their detox process, which today is very ineffective.”

The relapse rate is enormous, especially as time goes on — 90 to 95 percent.

Richard Pryor once said: “I’m not addicted to cocaine, I just like the way it smells.” There are many grains of truth in Pryor’s joke.

Cocaine influences the central nervous system; an accumulation of dopamine increases neural activity, causing euphoria. Then comes the desire to recreate the feeling. One experiences increasing insatiability requiring increasing amounts of the drug, hence the addiction.

“It’s a love that can be described as very erotic,” Yadid says. “One sniff of cocaine causes dopamine secretion that’s 10 times as much as in sex.”

The inability to erase the memory of the drug puts science and medicine in a dire situation, Yadid says. Doctors have no treatment that sustains a person for more than a year. Addicted people who seek rehab get replacement drugs and emotional support, but the overwhelming majority suffer relapses.

Yadid’s lab has spent more than two decades researching disorders linked to the brain’s recovery system, trying to develop unconventional treatments. He focused on changes in the brain of addicted people in order to understand how recovery processes fail.

“Basically, why go back to a drug after rehab? You take a person, treat him, clean him of the drug and put him in a place with good medical, social, rehabilitative and emotional support. The brain is supposed to forget about it over time and rehabilitate, but what really happens is an incubation of craving,” Yadid says.

“Time passes and the memory of the drug continues to tick in the brain. And the first time it’s exposed to something the addict associates with taking the drug — the environment, a smell, paraphernalia, a fellow drug taker — he returns to using it in increasingly greater doses.”

Rats on cocaine

The fragility of recovering addicts and their relapse potential are well known, but treatment programs end up increasing the craving. The upshot: Most programs do more harm than good.

In their latest research, Yadid and Moshe Szyf, a professor at McGill University’s Faculty of Medicine, tried to understand what lies behind rehab’s failure and the “incubation” of the craving for cocaine.

They trained rats to self-administer cocaine; every time the animals pushed a pedal and received the drug, they were exposed to a light and sound. Their craving was tested after 30 days of withdrawal.

The long withdrawal caused intense drug-seeking behavior that increased as the clean period went on. The craving was reawakened every time the light or sound associated with the experience was triggered, even when their bodies were clean.

“If during the addictive period they asked for the drug 20 times an hour, after three days of withdrawal they asked for it 200 times an hour. They simply didn’t stop pushing the pedal that gives them the drug,” Yadid says.

“Their craving for the substance grew even though their bodies were totally clean. A month of withdrawal for a rat is equivalent to five years for a person.”

Yadid and Szyf’s extraordinary answer led to the field of epigenetics, the study of hereditary changes in gene function that don’t involve changes in DNA sequence. These changes are usually associated with environmental effects.

Epigenetic change happens through a process called DNA methylation. Yadid and Szyf examined the epigenetic changes in the areas of the withdrawal mechanisms in the rats’ brains. They examined this both during the addiction process and during the animals’ withdrawal period.

“We activated a complicated system of bioinformatics. We scanned more than 30,000 genes and their 4 million versions,” Yadid says.

Setting genes right

To their surprise, they discovered that the most significant epigenetic changes didn’t happen during the intensive exposure to the drug. They happened during the withdrawal period. During that phase, hundreds of genes changed their state of methylation.

“The results showed that stopping the use of drugs causes the brain to respond feverishly — to the point that it reprograms the epigenetic landscape of the genome in the brain and allows the existence of only a pattern of addictive behavior,” Yadid says.

Fortunately, unlike the genes we inherit from our parents, which are fixed, epigenetic changes are reversible, through what Yadid calls “epigenetic treatments.”

In a follow-up experiment, the researchers found that injecting a methylation-inhibiting drug stopped the addictive behavior. In contrast, injecting a substance that increased methylation made the addictive behavior worse.

When they examined the changes in the brain after treatment they found that the substance that stopped addictive behavior returned addictive genes to a pre-addictive state.

These findings are only the start for Yadid and Szyf. They say epigenetic research has enormous potential to change treatment methods.

“These findings show that a completely new pharmacological approach of epigenetic inhibitors is needed,” Yadid says. He’s also researching other unconventional approaches to suppressing the craving for drugs; a raft of researchers across Israel are on board.

Findings of the research so far, which involved dozens of addicts in two Israeli drug rehab centers, have been published in the journal Addiction Biology.

The patients were treated with a substance known as DHEA — a steroid manufactured in the brain used in the United States as a nutritional supplement. The results were positive — after 16 months, 88 percent of the patients remained clean, compared with 62 percent in the control group.

Likewise, the patients showed improved decision-making after one month of treatment. These findings prompted the Health Ministry to consider using the supplement in the addicts’ treatment. The Israel Anti-Drug Authority funded the research.

“Our ability today to change attitudes about addiction to attain effective treatment over the long term is tangible and doable,” Yadid says. “The epigenetic approach is anchored in the obligation to provide real rehabilitation for addicts.”