Anti Addiction Drug Breaks Dopamines Vicious Cycle
Even by the standards of drug discovery, finding effective treatments for addiction has been a tough nut to crack. For cocaine addiction, for example, there have been dozens of trials of various pharmacological agents – dopamine antagonists, antidepressants, anticonvulsants, antipsychotics. But "not a single one with any proof of efficacy," Ivan Diamond told BioWorld Today.
Diamond, who is former vice president of neuroscience at Palo Alto-based biotech Gilead Sciences Inc. and now consults for the company, and colleagues at Gilead, the Medical University of South Carolina and the National Institute on Alcohol Abuse and Alcoholism, hope that they have found a strategy that will change that.
By inhibiting the enzyme aldehyde dehydrogenase 2, they were able to both reduce cocaine use and prevent relapse in animals addicted to cocaine.
Like many pharmacological approaches over the years, the compound Diamond and his colleagues are testing targets the dopamine system.
But "the elegance of what we've done is that we've moved away from the classical approach" of trying to inhibit dopamine receptors or dopamine synthesis, Diamond said. Instead, the strategy is to "restore the homeostasis" in the dopamine system that spins out of control in addiction.
Normally, drugs set off a vicious cycle in the addicted brain.
Dopamine, the neurotransmitter that is critical in good feelings in general, including those set off by addictive drugs, stimulates the rate-limiting step in its own synthesis by acting on dopamine auto receptors on dopamine-producing neurons.
In other words, "the more dopamine, the more receptors are stimulated to make more dopamine."
The compound that Diamond and his colleagues described, ALDH2i, short-circuits this spiral and replaces it with a negative feedback loop that prevents dopamine synthesis from going out of control in response to addictive drugs. The results were published in the Aug. 22, 2010, online edition of Nature Medicine.
"This drug seems to work on the basis of the intensity of the craving or need," Diamond said. "It is more powerful as an inhibitor the more you are addicted. The greater the craving, the more effective the drug."
Diamond and his team had previously published work showing that ALDH2 inhibitors can inhibit drinking and prevent alcohol relapse in animals. But "the interesting clue that came up in our work is that we were able to eliminate relapse even if the animals had not had alcohol," Diamond said.
Before that discovery, ALDH2 inhibitors were thought to be effective because they produce acetaldehyde, which "made you feel ill, so you wouldn't drink as much."
But because acetaldehyde is a metabolite of alcohol, the fact that ALDH2i was effective in the absence of alcohol meant that it must be working via another mechanism as well.
One advantage of the approach is that it has little if any effect on basal dopamine levels.
Blocking dopamine receptors or inhibiting dopamine synthesis, on the other hand, will interfere with normal pleasure because they lower dopamine levels without regard to whether the dopamine is mediating the normal pleasures of life or a drug binge.
Another is that Gilead researchers had demonstrated in earlier work that ALDH2 inhibitors add strong anti-anxiety effects.
"Let's say you are trying to stay off a drug," Diamond said. "One of the common denominators of . . . relapse situations is a lot of stress and anxiety." ALDH2 inhibition's strong anti-anxiety effects are likely synergistic with its ability to prevent dopamine synthesis from spinning out of control. "I think these add together to make a much more effective medication."
At this point, the approach is still in preclinical development, Diamond said. The compound used in the Nature Medicine experiments "was one of our earliest – by now we have much better ones." But nevertheless, the team still wants to "improve the drug so that it has better properties for clinical use."
He is optimistic that the company will be ready to approach the FDA within six months to a year. Whether clinical trials will be for patients with alcoholism, cocaine addicts, or both in parallel, is not clear yet.
Diamond hopes that the drug could ultimately become a weapon in the general practitioners arsenal, which is currently – well, sobering: "To me, that's one of the biggest problems we have as physicians," he said.
"The GPs are the one who see these persons first. They are identified as addicts – and then the docs don't know what to do," Diamond added.
Kudzu extract may treat cocaine addiction:
Mon, Aug 23 2010
WASHINGTON (Reuters) - An extract of the kudzu vine being developed to treat alcoholism may also help treat cocaine addiction, researchers at Gilead Sciences Inc reported on Sunday.
Tests on rats showed the drug could stop them from giving themselves cocaine, the Gilead team reported in the journal Nature Medicine.
Gilead inherited the experimental drug last year when it acquired CV Therapeutics Inc. A spokesman for the company said it was working to try to bring the drug to market.
"There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction," wrote Lina Yao, Ivan Diamond and colleagues.
Kudzu is an old remedy for alcoholism. The vine, native to Asia, has spread across much of the U.S. Southeast after being imported to control soil erosion.
CV Therapeutics made a synthetic extract called selective aldehyde dehydrogenase-2 inhibitor or ALDH2i. It carries the experimental name CVT-10216.
Tests on rats showed it could stop them from giving themselves cocaine. It can also prevent relapse after rats are weaned off cocaine.
They found how it works -- by raising levels of a compound called tetrahydropapaveroline or THP. Cocaine cravings make levels of a brain chemical called dopamine soar and THP interferes with this.
"We propose that a safe, selective, reversible ALDH-2 inhibitor such as ALDH2i may have the potential to attenuate human cocaine addiction and prevent relapse," the researchers wrote.
(Reporting by Maggie Fox; Editing by Cynthia Osterman)