Researchers at Yale University have identified a correlation between a gene variant and an individual’s required methadone dose, which may help clinics around the world more effectively treat substance abuse disorders.

Opioid abuse has reached epidemic proportions in the United States, where fatal overdoses from prescribed opioids alone have quadrupled since 1999. One of the most effective tools in treating opioid addiction is the drug methadone, a synthetic opioid that reduces craving without causing the patient to “get high,” according to Andrew Smith MED ’18, the lead author of the study. The ambiguity around appropriate dosage can cause a patient to receive either too small or too large a dose, both of which have dangerous consequences, Smith said. The researchers discovered a gene variant, found only in African-Americans, that may cause them to require more methadone for effective treatment.

“Most addictive disorders are genetically complex disorders, which means that they are the result of many different genetic variants,” said Henry Kranzler, director of the Center for Studies of Addiction at the University of Pennsylvania and co-author of the study. “We don’t even know the number of genes that are involved, but it is likely to be dozens.”

The paper, released in the journal Molecular Psychiatry on Jan. 24, is part of a larger project that has been in progress since the 1990s. In that time, the researchers involved have collected a significant amount of data on patients with substance abuse disorders, with the goal of identifying their genetic components, said Joel Gelernter, professor of genetics and neuroscience at the Yale School of Medicine as well as a co-author of the study. One of the principal study and data analysis methods they used, called a genome-wide association study, tests known variants across the genome for mathematical correlation with certain phenotypes, said Scott Cook-Sather, professor of anesthesiology and critical care at the Children’s Hospital of Philadelphia.

“The thing is, having already ascertained this large cohort of individuals, the opportunity to ask a series of questions related to opioid addiction arose,” said Smith. “For example, how does genetics affect efforts to treat people with opioid use disorders?”

For years, it was unclear why some patients require much higher doses of methadone to curb craving and withdrawal, Smith said. To investigate this uncertainty, he studied the GWAS and identified a gene variant that increases a patient’s required methadone dose. This variant was found very close to the gene OPRM1, which encodes the receptor targeted by methadone and other opioids.

In order for the scientific community to accept a finding like this, the study should be replicated again, Gelernter said. Despite calling researchers all over the world, the team was unable to find another research group with access to a sample with the necessary characteristics to make a replication of the exact same trait. However, they did come across a study that focused on the effectiveness of morphine as a painkiller for children, conducted by Cook-Sather and other researchers at the University of Pennsylvania. That study confirmed that the methadone dose-related variant identified in Smith’s study was also correlated with higher required morphine dose in children of African-American descent. The similarity in the results regarding both the gene variant and the racial background of the affected subjects further convinced researchers that they had identified a key genetic component involved in the body’s response to opioids, according to Smith.

Although the GWAS results indicate a significant association between the genetic variant and the patient’s therapeutic morphine dose, the biological mechanism remains unknown. The next step would be to investigate the molecular biology of how the gene variant affects necessary dosage, Cook-Sather explained. But the researchers agreed that if the results of those experiments confirm their findings, it would mean that adjusting methadone based on the presence of the variant could improve the effectiveness of substance abuse treatment.

“If you could specify beforehand what a person’s likely needed dose would be you could avoid the risk of either undertreating them, or overtreating them,” Kranzler said.

According to the National Institute on Drug Abuse, between 26.4 million and 36 million total people abuse opioids worldwide